Turkish Association for Psychopharmacology 4th International Congress on Psychopharmacology “Innovations and continuity in psychiatry & psychopharmacology: better care for better health” November 23-27, 2011 Antalya, Turkey www.psychopharmacology2011.org

ABSTRACTS OF THE INVITED SPEAKERS Abstracts of the Invited Speakers

OPENING CONFERENCE The evolution of human brain functions: Implications for psychobiological targets for well-being

Claude Robert Cloninger

Washington University, St. Louis, MO, USA E-mail: [email protected]

The natural building blocks of human personality are described based on the evolution of human brain functions (Cloninger, 2009; Cloninger, 2011). The phylogeny of human beings is traced from early vertebrates through mammals. The functional capacities that emerge along this lineage of ancestors are described. Comparative neuroanatomy is reviewed to identify the brain structures and networks that emerged coincident with the emergent brain functions. Neocortical development in mammals proceeded in 5 major transitions from early mammals to early primates, monkeys and apes, early humans, and modern Homo sapiens. These transitions provide the foundation for human self-awareness related to sexuality, materiality, emotionality, intellectual communication, and spirituality respectively. The evolution of functions in humans is compared to the psychobiological model of temperament and character previously described on the basis of individual differences in learning and genetic variation in human beings. The psychobiological model of personality provides a natural and thorough description of both the evolution and the development of personality in human beings. These evolutionary findings are related to clinical approaches to assessment and treatment of children and adults. Identification of the causal processes underlying well-being and ill-being is helpful in improving assessment and treatment in comparison to the frequent drop-out relapse rates obtained when diagnosis and treatment are based on symptoms, rather than their causes. Monitoring symptoms of illness and past lifestyle behavior has failed to promote change in well-being in a strong and consistent way in either individual care or public health. A clinician’s effectiveness in treatment depends substantially on his or her attitude toward, and understanding of, the patient as a person endowed with self-awareness and the will to direct his or her own future (Cloninger and Cloninger, 2011a). The causes of well-being operate as components of a virtuous circle of reciprocally interactive processes (Cloninger and Cloninger, 2011a) which evolved and develop in a stepwise manner. For example, emotions, cognitions, and actions have reciprocal interactions with one another. The induction of a positive mood by humor or kindness leads to a broadening of attention to be more inclusive and less defensive in thinking, which I have described as an outlook of unity (Cloninger, 2004; Cohn et al., 2009; Fredrickson, 2004; Fredrickson and Losada, 2005). In turn, an outlook of unity allows a person to cultivate greater self-acceptance, environmental mastery, and creativity, which in turn lead to greater health and happiness, thereby completing the self-reinforcing cycle. Positive emotional states can be induced by a variety of self-transcendent activities, such as acts of virtues, including cheerful humor, generosity, and humility (Cloninger and Cloninger, 2011b). Virtues interact with functional practices of well-being, including working in the service of others, letting go of fighting and worrying, and growing in awareness. In turn, virtues and self-regulatory functions interact with the body to promote human plasticity. Human beings probably show greater plasticity, and hence variability, than other animal species, which has allowed us to adapt to highly variable environmental conditions successfully. Key words: Cognition, emotionality, human characteristics, thinking, personality, character, health, happiness, wellness, well-being

References: 1. Cloninger, C.R., 2004. Feeling Good: The Science of Well-Being. Oxford University Press, New York. 2. Cloninger, C.R., 2009. The evolution of human brain functions: the functional structure of human consciousness. Australian and New Zealand Journal of Psychiatry 43, 994-1006. 3. Cloninger, C.R., 2011. The Phylogenesis of Human Personality: Identifying the Precursors of Cooperation, Altruism, and Well-Being. In: Sussman, R.W. and Cloninger, C.R. (Eds.), The Origins of Cooperation and Altruism. Springer, New York, pp. 63-110. 4. Cloninger, C.R., Cloninger, K.M., 2011a. Development of instruments and evaluative procedures on contributors to Illness and health. International Journal of Person-centered Medicine 1, in press. 5. Cloninger, C.R., Cloninger, K.M., 2011b. Person-centered Therapeutics. International Journal of Person-centered Medicine 1, in press. 6. Cloninger, C.R., Zohar, A.H., 2011. Personality and the perception of health and happiness. J Affect Disord 128, 24-32. 7. Cloninger, C.R., Zohar, A.H., Cloninger, K.M., 2010. Promotion of well-being in person-centered mental health care. Focus 8, 165-179. 8. Cohn, M.A., Fredrickson, B.L., Brown, S.L., Mikels, J.A., Conway, A.M., 2009. Happiness unpacked: positive emotions increase life satisfaction by building resilience. Emotion 9, 361-368. 9. Fredrickson, B.L., 2004. The broaden-and-build theory of positive emotions. Philos Trans R Soc Lond B Biol Sci 359, 1367-1378. 10. Fredrickson, B.L., Losada, M.F., 2005. Positive affect and the complex dynamics of human flourishing. Am Psychol 60, 678-686.

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S34 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

LECTURES

[KL-01] dependence during pregnancy: Balancing risk versus benefit

Peter Robert Martin

Departments of Psychiatry and , Vanderbilt University, Nashville, Tennessee, USA E-mail: [email protected]

Public health consequences of opioid dependence during pregnancy can only be inferred as increasing proportions of opioid-dependent women are addicted to non-medically prescribed analgesics and receive obstetrical care without being identified as addicted or treated. Because treatment recommendations for management of opioid dependence in pregnancy have primarily derived from studies in heroin- dependent pregnant women, there is a need to characterize and compare the clinical courses and complications of injection drug use (IDU) and non-medically prescribed . Intrauterine overdose or withdrawal and the neonatal abstinence syndrome (NAS) may occur regardless of the route of opioid administration; whereas other obstetrical complications are likely consequences of poor prenatal care/self- neglect typical for IDU. Methadone maintenance compared to active IDU is associated with improved prenatal care, increased fetal growth, reduced fetal mortality, decreased risk of HIV infection, decreased risk of pre-eclampsia, decreased NAS and reduced foster care placement; however, significant NAS is still observed in >50% of these births. Benefits of methadone maintenance during pregnancy for addiction to non- medically prescribed opioid analgesics may be attributed to support, structure, and prenatal obstetrical oversight compared to the stressful and chaotic lifestyle of active addiction. While methadone has been the standard of care for >40 years, the Schedule III (methadone is Schedule II) partial opioid buprenorphine merits examination in pregnancy because it has been found highly effective for treatment of opioid dependence, is associated with less severe withdrawal and is available in the U.S. under less severe restrictions than methadone. In the MOTHER study, maternal and neonatal outcomes of treatment with buprenorphine or methadone throughout pregnancy were compared in pregnant opioid-dependent women, in an international multi-center randomized, controlled, double-blind/double-dummy clinical trial (Jones et al., N Engl J Med 2010;363:2320-31). Although comparable numbers of methadone-exposed (57%) and buprenorphine-exposed (47%) babies required treatment for NAS, buprenorphine-exposed neonates required 89% less morphine to treat NAS; spent 43% less time in the hospital; and spent 58% less time in the hospital being medicated for NAS. The safety of opioid maintenance treatment during pregnancy must be judged in the context of comprehensive services (other than the administered per se) provided to addicted women by treatment programs. Buprenorphine is not inferior to methadone but may be preferable in terms of certain fetal outcome measures. Further research is needed to implement safe buprenorphine induction procedures in pregnant women, to balance reported teratogenic effects of opioids and benefits of opioid maintenance, and to determine the comparative safety and efficacy of methadone and buprenorphine for mother/fetus with co-occurring alcohol/benzodiazepine dependence or other psychiatric disorders and the psychoactive used to treat them. Key words: Opioid dependence, pregnancy, buprenorphine, methadone

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[KL-02] l-Benzylpiperazine, a major contaminant of ecstasy, induces marked changes in rat brain neurochemistry and behaviour

Alan Leslie Hudson1, Nubia Zepeda1, Amanda Perreault1, Maggie Lalies1, Glen Baker2

1Department of Pharmacology, University of Alberta, Edmonton, Canada 2Department of Psychiatry, University of Alberta, Edmonton, Canada E-mail: [email protected]

Ecstasy [(±) -3-4-methylenedioxymethamphetamine, MDMA] is a widely abused drug which in overdose can lead to serotonin syndrome. The patient presents with agitation, tremors, and muscle spasms, followed by hyperthermia which can lead to fatal organ failure. Recently ecstasy tablets have been found to contain piperazines, particularly 1-benzylpiperazine (BZP). The purpose of cutting ecstasy with BZP is to enhance the psychostimulant effects of MDMA. BZP is also marketed as a “legal high” in some countries; therefore some ecstasy tablets contain solely BZP. BZP is the active metabolite of an antidepressant drug, trelibet, which failed in clinical trials. There has been little study on the pharmacological effects of combining BZP with MDMA so we have investigated the bioavailability, neurochemistry and behavioral

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S35 Abstracts of the Invited Speakers profile of these drugs administered alone or in combination in rats. We have used the technique of brain microdialysis in rat frontal cortex, to monitor extracellular levels of noradrenaline, dopamine and serotonin in response to peripheral administration of BZP and MDMA. We were also able to monitor the animals for evidence of rodent serotonin syndrome. BZP (10mg/kg, i.p.) was able to elevate extracellular levels of dopamine, noradrenaline and to a lesser extent, extracellular serotonin in rat frontal cortex. MDMA (3mg/kg, i.p.) potently elevated extracellular serotonin and noradrenaline and to a lesser extent extracellular dopamine in frontal cortex. These neurochemical effects lasted for at least 2 to 3 hours relative to saline treated control animals. Combined BZP and MDMA administration led to markedly elevated extracellular levels of all three monoamines indicating the effects of the drugs were additive. BZP (10mg/kg, i.p.) caused marked behavioral activation, for example, increased locomotor activity and rearing behavior, whereas MDMA (3mg/kg, i.p.) resulted in flat body posture and less rearing. Similar to MDMA (3mg/kg, i.p.), BZP increased grooming, forepaw treading, sniffing and head weaving relative to saline injected animals. We also investigated a 5-HT2A antagonist, ketanserin (3mg/kg i.p.), to see if it could attenuate BZP- induced behaviors. Ketanserin alone had little effect on rat behavior but when co-administered with BZP, was able to decrease locomotion and rearing behavior. Interestingly, ketanserin had little effect on the increased sniffing and head weaving induced by BZP. At the doses of drugs used in this study hyperthermia was not apparent in any of the animals but we were able to measure blood and brain levels of BZP and MDMA hence we know bioavailability was not a problem. Overall, these results suggest that BZP and MDMA share certain psychopharmacological and neurochemical properties in the rat. Furthermore, combined administration of BZP with MDMA leads to a marked elevation of extracellular levels of all three monoamines in the frontal cortex rather than just serotonin which, if translated into the clinical setting, may explain the agitation and sympathomimetic toxic syndrome reported in some patients. All animal studies were conducted in accordance with the Canadian Council on Animal Care Guidelines and Policies with approval from the Animal Care and Use Committee in Health Sciences for the University of Alberta. This work is supported with a grant from Canadian Institute of Health Sciences. Key words: Ecstasy, (±) -3-4-methylenedioxymethamphetamine, 1-benzylpiperazine, serotonin syndrome, rat behaviour, brain microdialysis

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[KL-03] Unipolar versus bipolar depression in children: What do we know about the etiology, diagnosis, and treatment?

Rasim Somer Diler

Department of Psychiatry, University of Pittsburgh, PA, US E-mail: [email protected]

Bipolar disorder (BP) is a familial and recurrent illness that significantly affects the child’s normal development. BP is often manifested by periods of depression during which the child has significant psychosocial problems and increased risk for suicide. However, most clinical studies have focused on the manic phase of the illness. The depressed phase of the illness in youth is less recognized and less often treated than mania. Moreover, depressed youth with BP are more likely to have more severe depression, greater suicidality, and higher rates of comorbidities and functional impairment relative to depressed youth with major depressive disorder (MDD or “unipolar depression”). However, it is difficult to clinically differentiate the symptoms of BP depression from those of MDD. This issue is very important because youth with BP depression may be treated with antidepressants that can precipitate an episode of mania or mixed BP symptoms. Also, it may take up to 10 years from the initial symptoms of depression until BP is diagnosed and appropriate treatment is prescribed. Thus, early identification of BP youth, especially during depression, is critical not only to improve the long-term prognosis of BP, but also to prevent inappropriate treatments for BP youth. As demonstrated recently in BP adults, improving the accuracy of early diagnosis of BP in youth may be achieved by identifying objective neural biomarkers at an early age that are specific to BP and not common to MDD. Treatment guidelines for BD in children and adolescents were recently developed, but the panel left out depression and agreed that there was insufficient evidence to develop a treatment algorithm for it. Several studies suggest that there are effective and well-tolerated treatment options (e.g., lithium, mood stabilizers, second-generation antipsychotics [SGA]) for manic or mixed episodes of BD in youth; however, there are no maintenance studies in depressed children and adolescents with BP and available data for depressive episodes in BP is limited to one small randomized and two open-label acute treatment studies in adolescents. Management of depression is very different in BP depression than in MDD; antidepressants are widely used in MDD, but may exacerbate or induce mania and suicide in depressed BP youth. Antidepressant monotherapy is therefore contraindicated for the treatment of BP depression, and studies in depressed BP adults show that combining antidepressants with mood stabilizers may also not be effective. In conclusion, early differential diagnosis and treatment of depression in youth is a key factor to enable youth to follow a normal developmental path and prevent an unrecoverable loss in their development. Key words: Child, bipolar, depression, neuroimaging

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S36 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

[KL-04] Transcultural psychiatry: Practice and sample cases in USA and status in Turkiye

Alican Dalkilic

Virginia Commonwealth University, Richmond, VA & SEH, Washington, DC, USA E-mail: E-mail: [email protected]

Culture refers to unique behavior patterns and lifestyle shared by a group of people that distinguish it from other groups. The views, beliefs, values, and attitudes of a group characterize their culture. Culture and people influence and interact with each other reciprocally (1). In clinical practice patient’s culture, physician’s culture, and medical culture play a significant role. Adequate and appropriate understanding of cultural dimensions is essential for culturally competent practice (1). Also the impact of culture in evaluation and treatment of children and adolescents is significant in psychiatric patients (2). Cultural competency is a requirement for medical licensure in most states the US. To prove clinical competency clinicians are required demonstrate cultural competency. Clinicians typically work in multicultural and multiethnic societies (1). Ongoing globalization and interconnection of economies and rapidly spreading new social media platforms will increase diversity in all communities, but especially in developing countries including Turkiye. Therefore cultural competency training should be incorporated into residency training and continuous medical education systems especially for mental health clinicians. Clinicians should be familiar with culturally relevant relations and interactions of their patients (1), in order to establish therapeutic alliance and provide competent care and therapy besides demonstrating cultural sensitivity, knowledge, and empathy. Also most psychotherapies are based on Euro-American values of individualistic and egocentric concept, which can be contrasted with more sociocentric, ecocentric, and cosmocentric views (3). This issue should be taken into consideration when treating patients from other cultures or subcultures in the US and Europe. In this presentation I will review transcultural psychiatry practice in the US, provide and discuss some cases and summarize the status in Turkiye. Key words: Transcultural psychiatry, Turkish American cases, transcultural psychiatry in USA

References: 1. Focus, winter 2006 Vol. IV. No. 1, 81-89. Introduction: Culture and Psychiatry. Tseng W-S, Streltzer J. 2. Child Adolesc Psychiatr Clin N Am. 2010 Oct;19(4):661-80. Culture and development in children and youth. Pumariega AJ, Joshi SV. 3. Transcult Psychiatry. 2007 Jun;44(2):232-57. Psychotherapy and the cultural concept of the person. Kirmayer LJ

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[KL-05] Medical marijuana use in psychiatry

Tahir Tellioglu

Brown University, Rhode Island Hospital Dept Psychiatry, Providence USA E-mail: [email protected]

Medical marijuana refers to the use of parts of the cannabis plant or synthetic forms of specific as a physician-recommended form of medicine. The cannabis plant has been known to have medicinal use as an analgesic, appetite stimulant, antiemetic, muscle relaxant and anticonvulsant agent. A number of clinical studies, some disputed, claim that cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS) and analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette’s syndrome, epilepsy and glaucoma. Despite its illegality, patients have continued to obtain cannabis on the black market for self-medication for its self reported anti-anxiety or antidepressant effects. A survey of 3,000 patients in California from 1993-2000 revealed about 27% of individuals used it primarily for psychiatric conditions such as as an antidepressant or anxiolytic. Understanding the mechanisms of action of cannabinoids has revived therapeutic interest in these substances. However, clinical studies about the use of cannabis for psychiatric conditions are very limited. Further clinical trials, well-designed, carefully executed, and powered for efficacy, are essential to clearly define the role of cannabinoids in the treatment of psychiatric conditions. Key words: Medical marijuana, cannabis, psychiatric disorders

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DEBATES

[MD-02] Antidepressants are useful in the treatment of depression: the case for the motion

Ian Anderson

Neuroscience and Psychiatry Unit, University of Manchester, UK E-mail: [email protected]

The group of drugs we call antidepressants have been available for nearly 60 years and are the first available physical treatment for depression that became accepted by the public and clinicians alike. However in the last decade, associated with the rise of evidence- based medicine and a concern about the medicalisation of distress, there has been a questioning and re-evaluation of their efficacy and place in the treatment of depression. This has occurred against the backdrop of increasing distrust of ‘Big Pharma’ and emphasis on psychological treatment approaches. I will be addressing some of the main challenges that have been put forward questioning the usefulness of antidepressants, ranging from the denial that depression is a disorder that can be treated by physical means, to the argument that there is no pharmacological or empirical evidence for a clinically useful benefit over psychologically-mediated placebo effects. To do this I will touch on recent developments in the understanding of how antidepressants might directly influence the processing by the brain of emotional material, consider the evidence that direct pharmacological effects are necessary to maintain the therapeutic effects of antidepressants and review the empirical evidence for clinically important efficacy from treatment trials in depression. I will conclude that while antidepressants are certainly not a panacea, denying their place in treating depression is based on prejudice rather than objective appraisal of the evidence. Key words: Depression, antidepressants, placebo, efficacy

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[MD-02] Have clinically significant benefits of antidepressants been demonstrated?

Irving Kirsch

Associate Director, Program in Placebo Studies (PiPS) and Lecturer in Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Professor Emeritus of Psychology, University of Hull & University of Connecticut E-mail: [email protected]

Despite their widespread use, clinically significant benefits of antidepressants have not been demonstrated for most of the patients to whom they are prescribed. Meta-analyses of complete data sets consistently show a drug-placebo difference in improvement on the Hamilton Rating Scale for Depression (HAMD) of approximately two points, which is well below the 3-point difference set by the National Institute for Health and Clinical Excellence (NICE) as a criterion of clinical significance (1). Drug placebo differences increase with increasing severity of depression, but reach clinical significance only for 10% of the patients to whom they are prescribed (2). Defenders of antidepressants claim that depression scores are inflated by researchers who are anxious to qualify patients for clinical trials. To the extent that this is true, it compromises the clinical trial data leading to drug approval, but even if these trials are discarded, the absence of negative evidence does not constitute positive evidence of effectiveness. Discontinuation studies show a relapse rate of approximately 50% when patients are switched to placebo. However, approximately half of the relapses may be due to prior administration of the active agent. In extension trials, in which responders are kept on placebo, the relapse rate is only 25% (3). These data suggest that antidepressants might induce a biological vulnerability to relapse. Consistent with this hypothesis, a meta-analysis of tryptophan depletion studies indicates that the risk of becoming depressed after acute lowering of serotonin levels is greatest between three and six months after discontinuation of an antidepressant (4). It is also consistent with the results of the STAR-D trial, which was designed to be more representative than typical clinical trials of what happens in clinical practice. Following successful treatment in the STAR-D trial, 93% of patients either relapsed or dropped out of the trial within a year (5). Taken together, these data suggest that in the long run, rather than helping depressed people, antidepressants may make them worse.

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References: 1. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine [serial on the Internet]. 2008; 5(2): Available from: http://medicine.plosjournals.org/perlserv/?request=get- document&doi=10.1371/journal.pmed.0050045. 2. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta- analysis. Journal of the American Medical Association2010;303(1):47-53. 3. Andrews P, Kornstein S, Halberstadt L, Gardner C, Neale MC. Blue again: Perturbational effects of antidepressants suggest homeostasis in major depression. Frontiers in Psychology. [Original Research]. 2011;2. 4. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Molecular Psychiatry2007;12:331-59. 5. Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and Effectiveness of Antidepressants: Current Status of Research Psychotherapy and Psychosomatics2010;70:267-79.

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[MD-03] Antidepressants are useful in the treatment of bipolar disorders

Selçuk Kırlı

Department of Psychiatry, Uludag University, Bursa, Turkey E-mail: [email protected]

Using antidepressant drugs in Bipolar Depression (BD) has not been adequately considered or explored. This matter is indeed an area of ambiguity which should to be clarified as soon as possible due to the following facts concerning bipolar disorder: • It is repetitive and progresses relatively slowly • It tends to become chronic • It involves a high risk of suicide • It causes more disability than the other variations of the disease (1). Treatment manuals, expert views and practices do not fully agree with each other on the issue of whether or not it is appropriate to use antidepressant (AD) drugs to treat BD. There are also differences in the manuals of various countries although they have similar approaches. Americans and Canadians, in particular, strictly oppose the use of ADs in BD. They generally recommend using mood stabilizers (MSs) in treating less severe depressions, using ADs alongside these drugs only in severe depressions and discontinuing ADs as soon as possible. In Germany and some other countries, there is a long and firm tradition of using ADs as a first line treatment (2). Despite different approaches, it is a fact that the decision to use antidepressant drugs in BD is not easy. The difficulty might stem from a number of reasons including: • Studies supporting the effectiveness of ADs in BD are few in number and they are not sufficient to approve the use of ADs in this area. • Although the issue has not been supported by placebo-controlled studies, there is a common belief that ADs cause manic transitions and rapid cycles (3). The matters of debate that may clarify this issue can be summarized as follows (2): • Transition to mania and rapid cycling are significant phenomena in Bipolar Disorder (BD). • The issue of suicide is, in fact, of minimal importance in BD. • The efficacy of antidepressants in BD has not been supported by satisfactory evidence. • MSs having an AD effect in BD has been supported by satisfactory evidence. Here are some brief answers to the matters of debate: • Like ADs, MSs have also not been officially approved in the treatment of BD. It is worthwhile to discuss the new generation antipsychotics (NGAPs) which have been approved in this context. • The data on manic transition and rapid cycling are problematic for the use of tricyclics to a certain extent; the data obtained from modern antidepressants have largely removed this issue from being a special problem area. There are also other alternatives to diminish the risk (4). • The antidepressant effect is directed towards the syndrome, thus these drugs are also effective in BD, but there are no noteworthy positive data on this issue for MSs other than a slight benefit obtained from Lithium. • The issues of suicide and chronicity cause a greater risk than all other issues in terms of contribution to a bad result for BD. In view of these and similar benefit/risk comparisons, we can conclude that it is reasonable and necessary to use ADs as a single agent or in combination with MSs or NGAPs in the treatment of BD. This approach is already commonly applied in practice. Key words: Bipolar disorder, antidepressants, depression

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References: 1. Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwinn GM: Antidepressant for bipolar depression: A systematic review of randomized, controlled trials. Am J Psychiatry 2004;161:1537-1547. 2. Möller HJ, Grunze H: Have some guidelines fort he treatment of acute bipolar depression gone too far in the restriction of antidepressants? Eur Arch Psychiatry Clin Neurosci 2000;250:57-68. 3. Sachs SG, Nierenberg AA, Calabrese JR, Ketter TA, Marangeli LB, Milowitz DJ, Miyahara MS, Bauer MS: Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Eng J Med 2007;356:1711-1722. 4. Ghaemi SN, Rosenquist KJ, Ko YJ, Baldassano CF, Kontos NJ, Baldessarini RJ: Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry2004;161:163-165.

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JOINT SYMPOSIA

[JS-01] International Association for Cognitive Psychotherapy (IACP) Symposium title: Advances and problems in cognitive behavior therapy (CBT) Recent advances in the treatment of anxiety disorders

Stefan Hofmann

Department of Psychology, Boston University, Boston, USA E-mail: [email protected]

Cognitive behavioral therapy (CBT) is the first-line psychological treatment for anxiety disorders. Although effective, partial or non- response to treatment remains an all-too-common occurrence, with over half of patients failing to respond fully to first-line cognitive behavioral therapy. The same is true for pharmacological interventions for anxiety disorders. Combining CBT with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. This presentation will examine strategies to augment and modify CBT to enhance its efficacy. Recently, the search for new strategies to augment CBT has turned to a unique model of combination therapy. Rather than using pharmacotherapy as an anxiolytic in its own right, it is used to augment the core learning processes of cognitive-behavior therapy and exposure procedures. Moreover, recent work in emotion research points to new intervention strategies for anxiety disorders, such as mindfulness-based therapies and meditation practices. The first half of this presentation will review the current literature on conventional and novel combination strategies. A particularly successful prototype of a novel augmentation strategy of CBT is the use of d-cycloserine (DCS), a at the glycine recognition site of the glutametergic N-methyl-D-aspartate receptor, to facilitate extinction learning. The second half the presentation will review novel and adaptive emotion regulation strategies, including mindfulness and loving-kindness mediation. The efficacy of CBT for anxiety disorders can be enhanced by (1) augmenting the treatment with the cognitive enhancers such as DCS, and (2) modifying the intervention using novel emotion regulation strategies. The augmentation strategies are based on the fact that exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. In fact, animal studies have consistently shown that DCS facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. Positive findings so far have been reported in placebo-controlled trials for specific phobia, social anxiety disorder, panic disorder, and obsessive compulsive disorder. The strongest effects were observed in studies in which patients receive a small dose of DCS (50 mg) acutely 1 hour before the exposure trials with no more than 5 administrations weekly. The modification strategies of CBT have primarily focused on enhancing adaptive emotion regulation strategies, beyond traditional reappraisal strategies. Whereas cognitive reappraisal strategies are antecedent focused, these novel strategies are primarily emotion response focused. Although these strategies have only recently been studied as treatments for anxiety disorders, they are rooted in ancient Eastern and Buddhist practices. CBT is an evolving science that integrates traditional and modern approaches and is in line with modern emotion and neuroscience theories. Key words: Cognitive behavior therapy, anxiety disorders, combination drug therapy, NMDA, glutamate, mindfulness, meditation, emotion regulation

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S40 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Translating science into practice, collaborative empiricism and engagement in homework assignments in cognitive behavior therapy

Nikolaos Kazantzis

La Trobe University, Australia E-mail: [email protected]

Cognitive-behavioral therapy is more efficacious when between-session ‘homework’ tasks are included. Although the evidence for the effectiveness of homework appears compelling, only limited research is available to guide day-to-day practice. Recently, the search for strategies to enhance homework compliance (or engagement) has centered on practitioner competence in developing collaborative and empirical therapeutic relationships. Rather than viewing practitioner competence as a “trait”, newer measures are better equipped to capture the fluctuations in competence from session-to-session, as well as the relationship between therapist competence and patient compliance, and their combined effects on positive treatment outcomes. This presentation will use meta-analytic methods to review the empirical data demonstrating the causal and correlational effects of CBT homework assignments in enhancing positive treatment outcomes. Positive results have been obtained in the treatment of major depressive disorder, social anxiety disorder, panic disorder, and generalized anxiety disorder. Data supporting the development of therapeutic relationships characterized by strong patient and therapist involvement in the therapeutic work (collaboration) of identifying and evaluating the patients’ belief system (empiricism) will also be covered. A recent study in the treatment of major depressive disorder suggests that therapist competence in following a compliance enhancement protocol, which focused on collaborative empiricism, enhanced treatment outcomes. In conclusion, the results of these studies suggest that patient engagement with homework assignments is an important determinant of positive CBT outcomes, but practitioner competence may enhance the effect when the patient-therapist relationship is characterized by collaborative empiricism. Key words: Cognitive behavior therapy; homework assignments; therapeutic relationship; treatment outcome

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CBT as an evidence based treatment approach: Warning signs in therapy and common mistakes in daily practice

Mehmet Zihni Sungur

Medical School of Marmara University, Dept. of Psychiatry, Istanbul, Tukey E-mail: [email protected]

The remarkable results obtained from integration of cognitive and behavioral therapies and the simplicity and straightforward approaches of the treatment modality have attracted many therapists to practice cognitive-behavioral psychotherapy today. Unfortunately a considerable number of these therapists adhere to guidelines of a textbook-kind of therapy without formal training and adequate supervision, and therefore suggest standard package-type treatments with little or no attempt to develop individually tailored programmes. There are some crucial points that clinicians need to consider during the practice of CBT to increase positive treatment outcomes. This presentation will focus on significant points that should be taken into account during the daily practice of CBT, discuss common mistakes made in daily practice and the reasons why psychotherapy is devalued during delivery of psychological services, and suggest alternative ways to improve the efficiency of CBT for public care. Key words: Cognitive behavioral therapy, evidence based treatment, treatment principles and pitfalls

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Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S41 Abstracts of the Invited Speakers

[JS-02] Malaysian Psychiatric Association Symposium title: Malaysian perspective of substance dependence A harm minimization program against drug use and HIV problems in Malaysia

Rusdi Abd. Rashid1, Abdul Kadir Bin Abu Bakar2, Hazli Bin Zakaria3, Umi Binti Adzlin4, Mohammad Hussain Habil5

1University of Malaya Centre for Addiction Sciences(UMCAS), Kuala Lumpur, Malaysia 2Hospital Permai, Johor Bharu, Malaysia 3Dept. of Psychiatry, Hospital Universiti Kebangsaan Malaysia,Kuala Lumpur, Malaysia 4Dept. of Psychiatry, Kajang Hospital, Selangor, Malaysia 5Dept of Psychological Medicine,Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia E-mail: [email protected]

This symposium highlights the drug use and HIV situations in Malaysia from the perspective of the development of a harm minimization program, methadone assisted therapy for opiate dependents, and the world’s first integrated Islamic psychospiritual intervention with methadone treatment in a mosque setting. The speakers will present four topics that related to the drug problems in Malaysia. The first speaker will talk about harm minimization and the current drugs and HIV situations in Malaysia. The second speaker will highlight the harm reduction services available emphasizing pharmacotherapy options available in Malaysia, the challenges and future directions. The third speaker will focus on psychosocial intervention in particular an innovative psychospiritual intervention called the Spiritual Enhancement of Drug Addiction Rehabilitation (SEDAR) program in the Malaysian Ar-Rahman mosque. The fourth speaker will discuss Assisted Medication Therapy (AST) from an Islamic perspective. Harm minimization approaches in Malaysia are promising. However, the program needs large scale implementation and new strategies in order to make an impact on HIV/AIDS prevalence. New and larger platforms and more aggressive promotions are required to implement more harm minimization programs in the community. Key words: Addiction, harm minimization, HIV/AIDS, psychospiritual interventions

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S42

[JS-03] Hellenic Society for the Advancement of Psychiatry and Related Sciences Symposium title: Disorders of sleep and wakefulness and their pharmacological management Depression and the effect of antidepressants on sleep

Thomas Paparrigopoulos

Athens University Medical School, 1st Department of Psychiatry, Athens, Greece E-mail: [email protected]

Sleep mechanisms and the pathophysiology of depression are closely interrelated. Monoaminergic and neurotransmission are heavily involved in both. Therefore, it is not surprising that depression is almost invariably associated with sleep abnormalities. Several hypotheses have been advanced to explain their occurrence. One suggests that an increased pressure of REM sleep might be responsible. Another proposes that a deficiency in the mechanism responsible for non-REM sleep, as explained by the two-process model of sleep regulation, may be implicated. Finally, a third hypothesis suggests that an imbalance between the monoaminergic and cholinergic systems in the central nervous system (CNS) could be responsible for the pathophysiology of depression and the observed sleep aberrations. In principle, most antidepressants increase synaptic levels of norepinephrine, serotonin, and dopamine; yet they may also act on muscarinic and histamine (H1) receptors. These effects purportedly underlie their principal therapeutic mode of action, as well as their potential mechanism of altering sleep architecture. In this line of thought it has been proposed that central to the therapeutic effect

S42 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers of the majority of antidepressants is the observed strong and sustained suppression of REM sleep, without overlooking other factors involved in the mechanisms underlying treatment response. Moreover, tryptophan depletion and studies of selective serotonin reutake inhibitors (SSRIs) in sleep have shown that increases in serotonin levels could mediate the effect on REM sleep, which is often observed during antidepressant treatment. However, changes in non-REM sleep and sleep maintenance may be mediated through the action of other neurotransmitter systems. Although each antidepressant drug affects sleep architecture differently, there are some common features that characterize the various types of antidepressants. Thus, the majority of antidepressant drugs suppress REM sleep. Some, however, with little or no noradrenergic or serotoninergic reuptake inhibition, such as amineptine, tianeptine, nefazodone, trazodone, bupropion, and trimipramine, do not have clear-cut REM suppressant effects. Sleep continuity and total sleep time are improved with sedative medications, such as most tricyclic antidepressants (TCAs) and several antidepressants with 5-HT2c properties, such as mianserin, mirtazapine, nefazodone, and trazodone. On the other hand, most (SSRIs) and clomipramine, show evidence early in treatment of stimulating effects, thereby reducing total sleep time and sleep efficiency, and promote wakefulness. However, these effects are fairly short-lived and there are few significant differences among drugs after a few weeks of treatment. In conclusion, the majority of antidepressant drugs suppress REM sleep and increase REM latency, although this is not always the case. As far as sleep efficiency and total sleep time are concerned, antidepressants can be distinguished as either sedative or energizing agents. This individualized profiling of antidepressants provides a diversity of therapeutic options in terms of the management of concomitant sleep disturbances in depression. Key words: Depression, antidepressants, medication, sleep

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S42-3

Insomnia and the effects of hypnotics on sleep

Constantin R. Soldatos, Thomas Paparrigopoulos

Athens University Medical School E-mail: [email protected]

Insomnia is conceived as the subjective complaint of reduced sleep quantity and/or quality and affects a significant proportion of the general population. Approximately 10% of the population worldwide meet the full ICD-10 criteria for chronic insomnia. Insomnia is the outcome of the interplay of many environmental, biological, and psychological factors; consequently, its treatment should not only focus on ameliorating sleeplessness but should also address all those predisposing, precipitating and perpetuating factors that cause and maintain insomnia. Insomniacs need an integrative individualized management, which includes sleep hygiene measures, psychotherapeutic techniques, and the utilization of sleep-promoting drugs. The focus of treatment should be nighttime symptoms, the feeling of non-restorative sleep, and impaired daytime functioning as well. Benzodiazepine or benzodiazepine-like hypnotics (z-drugs) are still considered as the drugs of choice for the treatment of insomnia. However, due to their abuse potential, their pharmacological properties, and their widespread use (there are estimates that one of every four adults in developed countries takes sleeping aids at some time point during the year), it is highly recommended that the use of hypnotic drugs is restricted to the initial period of treatment mostly as adjuncts to other psychotherapeutic measures. Both types of hypnotics focus primarily on the inhibitory neurotransmitter GABA through binding to GABAA receptors; however, other neurotransmitter systems, such as the serotoninergic and , are also involved in the regulation of sleep-wakefulness and may be targeted by other compounds. The non-benzodiazepine drugs are generally preferred as a result of their improved binding selectivity and pharmacokinetic profile. However, their potential adverse effects, such as amnestic symptoms, next day residual sedation, and abuse potential, indicate the need for novel pharmacotherapies. In this line, agents acting on the melatonergic system and circadian mechanisms have been developed and approved for the treatment of insomnia ( and the agonist, ). Furthermore, a variety of other compounds targeting several neuroreceptors (i.e., GABAA agonism, melatonergic MT1/MT2 agonism, 5-HT2A antagonism, orexin receptor OX1/OX2 antagonism) are under investigation and may be added in the psychopharmacological armamentarium in the near future.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S43

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S43 Abstracts of the Invited Speakers

Hypersomnias and the effects of vigilance-promoting compounds

Antigone Papavasiliou

Department of Neurology, Pendeli Children’s Hospital E-mail: [email protected]

Hypersomnia is characterized by a propensity to fall asleep in situations when one is expected to be awake and alert. It may present with prolonged sleep episodes coupled with excessive daytime sleepiness (EDS) and frequent napping. It is described in narcolepsy, a neurological disorder characterized by EDS occurring with or without cataplexy; in idiopathic hypersomnia, also of central origin, characterized by EDS and episodes of prolonged nocturnal sleep; in recurrent hypersomnias, rare disorders manifesting with recurrent episodes of more or less continuous sleep (average duration of 1 week), recurring at highly variable intervals (one to several months), such as, Kleine–Levin syndrome and menstrual-related hypersomnia. Chronic sleep loss and/or poor sleep quality may be underlying reasons for EDS; these occur in numerous sleep disorders, such as obstructive sleep apnea (OSA) and in psychiatric disorders, particularly depression. Approximately 80% of depressive states are associated with insomnia; patients do not necessarily have a higher propensity to fall asleep in daytime but report subjective sleepiness that differs from the EDS encountered in narcolepsy and OSA. There are also hypersomnias attributable to other medical conditions, drugs, or substances, as well as behaviorally induced hypersomnia caused by insufficient time to sleep. Transition between sleep and wakefulness is simply described as oscillations between two opponent processes, one promoting sleep, another promoting wakefulness. The complex neurobiological mechanisms and the neurotransmitters and neuromodulators underlying these processes, including noradrenergic, , cholinergic, , and histaminergic systems and more recently, the hypocretin/orexin and dopamine systems, have been established. The mechanisms of action of some vigilance-promoting agents are as follows: psychostimulants act through enhanced dopamine action (amphetamines, methylphenidate) or acetylcholine action (caffeine); modafinil may act through enhanced central histamine, hypocretin, and possibly dopamine action; γ -hydroxybutyrate (GHB), acts on GABA and GHB receptors. EDS in narcolepsy is traditionally treated with psychostimulants; these are rarely effective in idiopathic hypersomnia, although this was not examined through randomized controlled trials. Modafinil, a first-line wakefulness-promoting medication, is a useful alternative to psychostimulants for EDS in narcolepsy (Level I evidence). It may be effective for EDS due to idiopathic hypersomnia (one Level IV study and expert consensus). It is not associated with rebound hypersomnolence, cardiovascular problems, or abuse potential, as may be seen with amphetamines. Modafinil alleviates sleepiness and fatigue in shift work disorders, residual sleepiness in treated sleep apnea syndrome, multiple sclerosis, Parkinson’s disease and depression. It is promising as an alternative to psychostimulants for excessive fatigue associated with medical and psychiatric disorders and as an augmentation medication for treatment-resistant depression. Due to rare serious complications (allergic and psychiatric), the EMA concluded that its benefit/risk balance was positive for narcolepsy but negative for other sleep disorders and neurological diseases, including idiopathic hypersomnia. The FDA has approved it for EDS in narcolepsy, shift work sleep disorder, and OSA. In narcolepsy, GHB at bedtime reduces nocturnal awakenings, increases stage 3 and 4 sleep, and consolidates REM sleep periods; these effects coincide with improvement in daytime symptoms, including cataplexy. Key words: Vigilance-promoting agents, hypersomnia, psychostimulants, modafinil, γ -hydroxybutyrate

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S44

[JS-04] The International Union of Basic and Clinical Pharmacology (IUPHAR) Symposium title: Pharmacogenomics of psychoactive drugs Role of polymorphic drug transporter in treatment-resistant depression

Tanja Brueckl, M. Uhr

Max Planck Institute of Psychiatry, Germany E-mail: [email protected]

To be effective antidepressants and other centrally acting drugs have to penetrate the blood-brain barrier. Transport proteins such as p-glycoprotein that are located at the BBB do not only transport toxic substances but also many drugs back into the blood. In preclinical animal models and a study examining more than 400 patients, the relationship between polymorphisms in the ABCB1 gene coding for p-glycoprotein and the clinical efficacy of antidepressants could be demonstrated. With respect to those antidepressants that are

S44 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers substrates of p-glycoprotein there is a significant statistical relationship between polymorphism and remission rate after 4 to 6 weeks. Clinically, genetic analysis of ABCB1 polymorphisms may be used to predict how likely it is that a patient will respond to therapy with antidepressants or other centrally acting drugs. This in turn will help to select the right drug and/or dosage (Neuron 2008, 57:203-209). Further data from a preliminary pilot study suggest that the treatment of depression could be optimized by a routine application of an ABCB1 gene test. Patients carrying the less favourable ABCB1 genotype with respect to the clinical efficacy of antidepressants may especially benefit from a dosage increase. P-glycoprotein in the membrane of vascular cells causes centrally acting drugs such as citalopram, paroxetine, venlafaxine and others to be transported from the brain back to the vascular lumen. If the protein is missing or if its function is impaired, more drugs pass from the blood into the brain. Depending on changes (polymorphisms) in the ABCB1 gene, p-glycoprotein allows varying amounts of a drug to pass into the CNS.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S44-5

Relationship between pharmacogenetics and personality traits: Relevance for suicide

Adrián Llerena

International Union of Basic and Clinical Pharmacology (IUPHAR), Extremadura University Hospital E-mail: [email protected]

CYP2D6 genetic polymorphism is related to variability of the enzyme’s hydroxylation capacity. Subjects carrying zero CYP2D6 active genes are classified as Poor Metabolizers (PMs). The rest are Extensive Metabolizers (EMs) with one or two active genes, including a group of Ultra-rapid Metabolizers (UMs) with more than two active alleles. UMs have a hydroxylation capacity more than 100 times higher than PMs. The frequency of PMs and UMs in Spain is 7-10% and 4.9%, respectively (Llerena et al., 2009). A higher frequency of UMs has been found among individuals who committed suicide vs. those who died from natural causes (Zackrisson et al, 2010). One explanation for this relationship could be treatment failure with antidepressant drugs metabolized by CYP2D6 (fluoxetine, paroxetine, fluvoxamine, venlafaxine, citalopram, etc.) (Llerena et al., 2004; Llerena et al., 2009) widely used to prevent suicide or to treat mood disorders. A complementary explanation could be via the implication of the polymorphic CYP2D6 in the endogenous metabolism. Since we found an association between this drug metabolizing enzyme and psychological functioning, CYP2D6 has been associated with behavioral and clinical risk factors such as personality and vulnerability to psychopathology (Llerena et al., 1993; Llerena et al., 2007; Gonzalez et al., 2008; Peñas-Lledó et al., 2009, Peñas-LLedó et al., 2010). These two hypotheses could explain the relationship found between CYP2D6 and suicide (Peñas-LLedón et al 2011, in press) The biotransformation of several antidepressants and antipsychotic drugs is mainly determined by genetic factors mediating the CYP2D6 gene polymorphism. Additionally, the potential interaction between CYP2D6 and endogenous metabolism must be taken into consideration due to its potential implication for personality traits (LLerena et al 1993; Gonzalez et al 2008) and functioning, such as: neurocognition (Peñas-Lledó et al 2009) and psychopathology, eating disorders (Peñas-LLedó et al., 2010) and suicide (Peñas-Lledó et al., 2011). In summary, the pharmacogenetics of CYP2D6 may be a useful tool to predict unexpected side-effects, interactions, or therapeutic failures of many relevant drugs and may explain the interethnic differences oberserved in the response to psychotropic drugs, but also vulnerability to psychopathology including suicide.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S45

Genetic causes of hypersensitivity to antipsychotics – the clozapine story

Ingolf Cascorbi

Institute of Experimental and Clinical Pharmacology, University of Kiel, Germany E-mail: [email protected]

Clozapine is considered to be the most efficacious drug to treat schizophrenia, but despite these benefits, clozapine prescriptions comprise only 2-10% of the total antipsychotic market for schizophrenia in the United States. It was introduced on the market in 1971 but was withdrawn in 1975 after reports of clozapine-induced agranulocytosis (CIA) in Finland. Due to its high efficacy in treatment-resistant schizophrenia, it was reapproved in 1990 by the FDA and health authorities in most other countries; however, regular hematological

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S45 Abstracts of the Invited Speakers monitoring was required. The implementation of this monitoring system has successfully reduced the incidence of CIA from 1.3% to 0.4%. Currently 239 cases of agranulocytosis are registered at the FDA adverse drug reaction data bank. There have been certain attempts to predict agranulocytosis by genetic association studies in particular in the NADPH myeloperoxidase complex (1) and FC-gamma receptors (2). We could identify an association to the polymorphic myeloperoxidase, responsible for oxidative reaction in neutrophils. More recently, confirmatory studies in two independent cohorts of 33 and 49 CIA cases and 54 and 78 controls indicated that markers in the HLA system are highly significantly associated with the risk of CIA. HLA-DQB1 6672G>C was associated with CIA conferring an odds ratio of 16.9 (3). Currently a large consortium led by Duke University has aimed to collect a large sample of well defined cases of CIA in order to allow genome-wide association studies. Key words: Clozapine, agranulocytosis, NADPH-oxidase, myeloperoxidase, HLA-system, genetic association

References: 1. Mosyagin I, Cascorbi I, Schaub R, Krüger T, Dettling M. Drug-induced agranulocytosis: impact of different fcgamma receptor polymorphisms? J Clin Psychopharmacol. 2005;25:435-40. 2. Mosyagin I, Dettling M, Roots I, Mueller-Oerlinghausen B, Cascorbi I.. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol. 2004;24:613-7. 3. Athanasiou MC, Dettling M, Cascorbi I, Mosyagin I, Salisbury BA, Pierz KA, Zou W, Whalen H, Malhotra AK, Lencz T, Gerson SL, Kane JM, Reed CR. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry. 2011;72:458-63.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S45-6

[JS-05] Indian Psychiatric Society Symposium title: Current concept of obsessive compulsive disorder (OCD) Current understanding of the concept of obsessive compulsive disorder

Manickam Thirunavukarasu

Professor & Head, Department of Psychiatry, SRM MC & RC, Kattankulathur, 603203, India E-mail: [email protected]

Obsessive-compulsive disorder (OCD) is a relatively common disorder, occurring in around 2-3% of general population. In the past century, the understanding of the disorder has improved and has been clearly delineated as a valid nosological entity. The heterogeneity of the disorder has been explained based on various phenotypic subtypes. Factor analytic studies have provided consistent evidence that distinct obsessive-compulsive symptom dimensions exist, including obsessions/checking, contamination/washing, symmetry/ordering, and hoarding. It has been hypothesized that each symptom dimension may be underpinned by a distinctive set of bio-behavioral mechanisms. There has been a good deal of interest recently in the disorders characterised by similar phenomenology and psychobiology called obsessive compulsive spectrum disorder (OCSD). These include tic disorder, body dysmorphic disorder, impulse control and eating disorders. In view of all these changes in understanding and newer conceptualisation, OC(S)D might find a separate place for itself in the DSM V and ICD 11, rather than being classified under anxiety / neurotic spectrum disorders.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S46

Biological theories of obsessive compulsive disorder

A. Shyam Sundar

Assistant Professor, Department of Psychiatry, SRM Medical College Hospital and Research Centre, Kattankulathur, 603203, India E-mail: [email protected]

Although the pathophysiology of OCD is still far from resolved, the existence of a biological basis for OCD has been clearly established. Twin, family, segregation and linkage studies have demonstrated that genetic factors contribute to the pathogenesis of OCD. There

S46 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers is a general consensus that fronto-striato-thalamo-cortical dysfunction is the neuronal basis of obsessive-compulsive disorder. The differential response of OCD to clomipramine and SSRIs, compared to other antidepressants, has led to the primacy of the serotonin (5HT) hypothesis of OCD. Currently serotonin has also been implicated in the pathophysiology of other OC spectrum disorders. However, several lines of research suggest that the dopamine system, with which 5HT interacts, may play a major role in the expression of OC symptoms. Recent genetic and neurochemical studies also implicate glutamate in the pathophysiology of OCD. The recognition of PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) has increased the interest in the possibility of an immune-mediated pathophysiology of obsessive-compulsive disorder. In this presentation, these recent advances in biological models of OCD will be discussed.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S46-7

Psychopharmacological and somatic interventions for OCD

Kandasamy Arun

Assistant professor, Department of Psychiatry, SRM Medical College & Research Center, Kattankulathur, 603203, India E-mail: [email protected]

OCD was initially thought to be unresponsive to treatment but subsequently, a range of effective treatments has been developed on the basis of two approaches, pharmacological and psychosocial. Pharmacological agents such as Selective Serotonin Reuptake Inhibitors (SSRIs) and clomipramine have changed the face of OCD management. Around 50–60 % of patients showed remission after treatment. In treatment resistant cases, augmenting agents like clonazepam, risperidone and buspirone are used. Intravenous clomipramine is another option. Other strategies which are currently under study include riluzole and other drugs which act on the glutaminergic system, opioid and inositol augmentation. Immunomodulatory therapies have also been studied especially in PANDAS. Development of newer somatic methods of treatment like repetitive trans-cranial stimulation (rTMS) and Deep Brain Stimulation (DBS) are promising in targeting the fronto-striato-pallido-thalamo-cortical circuits for treatment resistant OCD. Although controversial, stereotactic and gamma knife assisted neurosurgical procedures such as cingulotomy and anterior capsulotomy are also possible treatments for resistant cases.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S47

Psycho-social interventions for OCD

Manickam Thirunavukarasu

Professor & Head, Department of Psychiatry, SRM MC & RC, Kattankulathur, 603203, India E-mail: [email protected]

We will review recent advances in the psychological treatments for obsessive compulsive disorder. In the early 20th century, psychological treatment for OCD consisted largely of psychodynamic psychotherapy. The general consensus of that era was that OCD was an unmanageable condition with a poor prognosis. Starting from the 1950s, laboratory studies on extinction of conditioned responses followed by clinical research led to the formulation of Exposure and Response Prevention (ERP) for OCD.We have developed a model combining ERP and CBT. This behavioral approach currently is the first-line intervention for adult obsessive-compulsive disorder. Recently predominantly cognitive approaches have been evaluated to overcome the shortcomings of ERP. Methodologically rigorous controlled trials have suggested that the benefits from CBT exceed those from placebo and attention-control conditions and have similar or greater efficacy than serotonergic monotherapy. The clinical predictors for response to CBT include symptom severity, symptom subtype, severe depression, the presence of comorbid personality disorders, family dysfunction and the therapeutic alliance. Combination treatment with pharmacotherapy has generally revealed promising results. Nevertheless, more studies are still needed in certain areas. We will explain in detail how we practice in our patients and the results.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S47

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S47 Abstracts of the Invited Speakers

[JS-06] Czech NeuroPsychopharmacological Society (CNPS) Symposium title: From models of schizophrenia to clinical outcome: A psychopharmacological perspective Safety first, efficacy second? Fear and the need for treatment in the absence of controlled data

Pavel Mohr, David Hnidek, Dagmar Seifertova

Prague Psychiatric Center, Czech Republic E-mail: [email protected]

In clinical practice, physicians are routinely asked to make decisions about whether to initiate or continue antidepressant treatment in a situation where no safety data are available. Pregnancy and breast-feeding can serve as an example, where controlled clinical trials provide little guidance. Females of fertile age are rarely included in the early phases of clinical testing, indeed, Phase IIb and III trials have a standard provision to use a reliable method of contraception. Pregnancy during a drug trial is considered as a ‘serious adverse event’ with subsequent study discontinuation. The reasons are not just ethical and legal but also marketing, including the drug manufacturers’ fear of having their products associated with potentially grave side effects, such as malformations. Drug treatment in pregnancy and lactation thus pose a highly relevant clinical problem that cannot be addressed in controlled trials. Excessive concerns of negative consequences could erroneously result in a generalized recommendation to not get pregnant or to abort an existing pregnancy. However, the fetus may already have been exposed to drugs early in the first trimester during frequently unplanned pregnancies; in addition, recent epidemiological data indicate increasing consumption of psychotropics, including antidepressants, by pregnant women. Psychiatrists have to weigh the known risks of treatment discontinuation versus the potential risks for the fetus and infant. They should also consider whether alternative non-pharmacological interventions (psychotherapy, ECT, rTMS) are accessible or effective. The only available safety data on antidepressants come from animal studies, epidemiological trials, drug registries, case series, anecdotal case vignettes and clinical observations. Moreover, published findings have to be viewed with caution and interpreted correctly. For example, recent data suggested an increased teratogenic risk for the antidepressant paroxetine. While it is true that a meta-analysis confirmed an increased relative incidence of malformations, the absolute risk was raised from 3% to 4% for all congenital malformations and from 1% to 2% for cardiac malformations. In 2005 the Prague Psychiatric Center established a specialized consultation outpatient center for pharmacotherapy in pregnancy and breastfeeding. The center provides services and information on safety and treatment recommendations directly to patients, their treating psychiatrists and other physicians as well. The database consists of patients records, data on their illness, treatment and pregnancy outcome. Currently, a prospective study for the longitudinal follow-up of offspring exposed in utero to psychotropics has been designed. The focus is on their developmental milestones, physical health, neuropsychological performance and general well-being. Key words: Psychotropic drugs, pregnancy, lactation, drug safety, psychiatric disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S48

Basic concepts of schizophrenia: Experimental approaches

Cyril Höschl1

1Prague psychiatric centre, Centre of neuropsychiatric studies, 3rd Medical faculty, Charles University, Prague, Czech Rep. E-mail: [email protected]

One of the crucial questions in the study of schizophrenia is, whether the diagnosis of the disease represents one entity or a group of disorders (“Gruppe der Schizophrenien”). Nancy Andreasen suggests the term “lathomenology” for a bottleneck on the pathogenetic way from various possible etiological factors to diverse phenomenological expressions (symptoms) (Arch Gen Psych 1999;56:781-787). In the background of this common denominator, there is an anatomical and functional disruption in neuronal connectivity and communication, which can be a consequence of incomplete or erroneous neuron formation, migration, synaptogenesis or pruning during ontogenesis. Also apoptosis and activity dependent changes might play a role in this development. This all can happen from conception to early adulthood and can lead to the impairment in fundamental cognitive functions. This leads to the development of clinical symptoms, either positive or negative. Schizophrenia can be regarded as a “disconnection” or “information processing disorder”. There are many

S48 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers neural circuits, where the clinical impact of the disconnection or misconnection is worthy of study. One of them is the fronto-thalamo- cerebellar circuit with the special role of the cerebellum not only in the synchronization of motor processes, but also in the coordination of motor-cognitive sequences. The disconnection of these circuits leads to “cognitive dysmetria”. Mezo-cortical pathways also represent a crucial pathogenetic point. fibers from the ventral tegmental area to the pre-frontal cortex are under serotonergic inhibition via 5-HT2 receptors. This configuration can help in the understanding of the dual mode of action of novel antipsychotic agents, which are effective in both positive (hyperdopaminergic state in mezo-limbic areas) and negative (hypodopaminergic state in prefrontal cortex) symptoms. Disconnection can play a role also in circuits involved in executive functions (fronto-parieto-temporo-cingulate). On the neurochemical level, many imbalances in information processing can be explained by the framework of Carlsson’s scheme of psychotogenic pathways. The crucial mechanism involves striato-thalamic GABA-ergic control of gating, which is under control from cortex. The scheme can also explain the amphetamine model of psychosis, the dopamine hypothesis of schizophrenia, the glutamatergic model of schizophrenia and the psychotogenic effects of hallucinogens (LSD), atropine, phencyclidine etc. Our own study on the role of serotonin regulation of psychotogenic pathways will be reported (Bubeníková et al., The effect of tryptophan depletion on the action of haloperidol in MK-801 treated rats. Eur J Pharmacol, 2004; 502, 1-2:109-116). The background of disconnection may involve gene-environment interaction including early neuroinfection (inflammatory process). The classical antipsychotic drugs exert primarily antidopaminergic properties, which are responsible also for their side-effects such as hyperprolactinemia and extrapyramidal syndrome. Nevertheless, psychotogenic pathways in the brain involve several different mechanisms, which could serve as targets of antipsychotic modalities, e.g., facilitation of glutamatergic neurotransmission, blockade of serotonin 5-HT2A receptors, expression of BDNF and bcl2, inhibition of GSK-3β phosphorylation and thus apoptosis etc. Key words: Schizophrenia, glutamate, dopamine, serotonin, information processing disorder, gating

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S48-9

The ins and outs of the human model of schizophrenia

Jiri Horacek1, Vera Bubenikova Valesova1, Tomas Palenicek1, Filip Spaniel2, Cyril Höschl1

1Prague Psychiatric Center, Prague, Czech Rep. 23rd Medical Faculty of Charles University, Prague, Czech Rep. E-mail: [email protected]

The experimental models of schizophrenia are based on morphological, biochemical and genetic findings in the clinical population. These models serve as an important tool for the research of etiology and pathophysiology, and for testing novel potential treatment methods. The experimental models of schizophrenia are divided into neurodevelopmental, pharmacological and genetic. Only the pharmacological model is useful in humans. An important role of the glutamatergic neurotransmitter system in the pathogenesis of schizophrenia has been supported by findings on various levels from molecular interactions up to the structural layout of the neuronal network in the human brain. The research of the glutamatergic system in schizophrenia has advanced with the use of non-competitive antagonists of glutamate NMDA receptors (phencyclidine, ketamine, and dizocilpine). These compounds change both human and animal behavior and induce schizophrenia-like manifestations in the field of different neurobiological modalities and markers. The models based on both acute and chronic administration of non-competitive antagonists of glutamate NMDA receptors in humans and rats show phenomenological validity and are suitable for searching for new substances with antipsychotic effects. In particular, the human model of schizophrenia based on infusion of ketamine exerts high face validity in term of induction both positive and negative symptoms, and characteristic cognitive, electrophysiological (qEEG) and metabolic (PET) changes. Nevertheless, the pathophysiology of schizophrenia remains unexplained. In the light of the neurodevelopmental model of schizophrenia based on the early administration of NMDA receptor antagonists, it seems that increased cellular destruction by apoptosis or changes in function of glutamatergic NMDA receptors in the early development of the central nervous system are decisive for subsequent development of psychosis, which often does not manifest itself until adulthood. Chronic administration of NMDA (not applicable in humans) antagonists initializes a number of adaptation mechanisms, which correlate with findings obtained in patients with schizophrenia; therefore, this animal model is necessary for research into the pathophysiology of this disease. This work was supported by project 1M0517 from the MEYS Czech Republic Key words: Schizophrenia, models, NMDA receptors, ketamine, glutamate, neurodevelopment

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S49

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S49 Abstracts of the Invited Speakers

[JS-07] Canadian College of Neuropsychopharmacology Symposium title: Advances in psychotropic drug development: Promising novel targets and agents for psychiatric disorders Recent advances in the neurochemistry of schizophrenia and potential targets for antipsychotic drug development

Serdar Dursun, Glen Baker, Marnie Mackay

Neurochemical Research Unit, University of Alberta, Edmonton, Canada E-mail: [email protected]

The dopamine hypothesis of schizophrenia has been a major influence for many years in stimulating research in schizophrenia and in assisting in the development of antipsychotic drugs. However, it has become obvious that other neurotransmitters and/or neuromodulators must also be involved. The antipsychotic drugs currently available are far from ideal and there is an urgent need to continue to search for new targets for potential antipsychotics. Much of the recent research on non-dopaminergic systems has focused on the amino acids glutamate and GABA, with the bulk of the results suggesting hypofunction of both in schizophrenia. Glutamate does not pass the blood-brain barrier readily and studies conducted to develop drugs that act at one or more of its multiple receptors have not, to our knowledge, yet produced potential new effective antipsychotics. Two other amino acids, glycine and D-serine, co-agonists at the NMDA glutamate receptor, have received considerable attention, and administration of these amino acids, usually in conjunction with currently available antipsychotics, have been reported in some studies to result in improvement of some symptoms of schizophrenia. However, these amino acids have to be administered in relatively high doses which may result in side effects such as peripheral neuropathies. There is now a great deal of interest in testing drugs that inhibit their uptake by neurons and/or glial cells (astrocytes and activated microglia), thus making increased levels of these amino acids available to interact with the NMDA receptor or, particularly in the case of D-serine, altering metabolism of the amino acid. This research also emphasizes the importance of glial cells. Microglia are also involved in immune responses and when activated release a number of proinflammatory cytokines that can result in some behavioural, cognitive, and neuroendocrine changes characteristic of schizophrenia. It is also of interest that there is now research indicating that there may be a dysfunction of oligodendrocytes and myelination problems in schizophrenia. Another exciting area of research with regard to schizophrenia is in the study of neuroactive steroids, rapid acting steroids which can act as positive or negative allosteric modulators at several types of neurotransmitter receptors, most notably GABA-A receptors and NMDA receptors. Plasma levels of several of these steroids are altered in a number of psychiatric disorders, including schizophrenia and some clinical studies suggest that pregnenolone may be a useful adjunctive agent in schizophrenia. Brain levels of some of these steroids have also been reported to be altered in laboratory animals following administration of currently available antipsychotics. In addition to the compounds mentioned above, potential interventions which may be added to the usual antipsychotic treatments include lamotrigine and minocycline. Furthermore, modulation of the nitric oxide pathway continues to gain considerable interest as a possible therapeutic target in the treatment of schizophrenia. We will report the results of an RCT double-blind crossover study on the addition of L-arginine, the precursor amino acid for nitric oxide, to usual treatment with antipsychotics in schizophrenic patients. Key words: Schizophrenia, antipsychotic development, glutamate, nitric oxide, D-serine, glycine, glia, neuroactive steroids

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S50

Advances in antidepressant targets and drug development

Glen B. Baker, Nicholas D. Mitchell, Jean Michel Le Melledo, Serdar Dursun

Department of Psychiatry, University of Alberta, Edmonton, AB, Canada E-mail: [email protected]

The hypothesis of depression, which suggests that depression is the result of a functional deficiency of noradrenaline (NA) and/or serotonin (5-hydroxytryptamine, 5-HT) at certain synapses in the brain, has had a major influence on research into the neurochemistry of depression for over fifty years, and most of the antidepressants currently available have an effect on one or both of these biogenic amines. However, it was obvious early on that other neurotransmitters or neuromodulators must also be involved, and the

S50 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers search continues for other targets that may give clues for the development of future antidepressant drugs that are effective in a greater number of depressed patients, are faster acting and have an improved side effect profile over those currently available. Some of those targets will be discussed in this overview. The amino acids γ-aminobutyric acid (GABA) and glutamate are major inhibitory and excitatory neurotransmitters, respectively in the brain, and a delicate balance between them must be maintained for normal brain function. Research on GABA at the animal model and clinical levels implies a GABAergic deficit in depression, and animal studies and the rapid antidepressant action of intravenous ketamine in human subjects suggest hyperglutamatergia in depression, although the results of some neuroimaging studies to date do not seem to support these ideas. In recent years, there has been a great deal of interest in the possible roles of neuroactive steroids (rapid acting neurosteroids which can act as positive or negative modulators of a number of neurotransmitter receptors, most notably GABA-A and NMDA glutamate receptors) in the etiology and pharmacotherapy of depression. Allopregnanolone has received particular attention in this regard. Several researchers have proposed that the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the etiology of depression and there has been considerable interest in corticotropin-releasing hormone (CRH) receptor antagonists as potential antidepressants. The peptide substance P acts on neurokinin 1 (NK1) receptors, and there is ongoing interest in NK1 receptor antagonists as potential antidepressants. The role of the immune system in depression has been the focus of considerable research and it has been proposed that excessive proinflammatory cytokines (which are released by activated microglia) may result in depressive symptoms; it is of interest that such cytokines can activate CRH release and reduce levels of 5-HT in the brain. Although there are some contradictory results, several studies suggest that antidepressants increase expression of cyclic AMP-regulated element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Dysfunction of melatonin secretion in depression has been suggested and this may account, at least in part, for sleep disorders experienced by many depressed subjects. , a melatonin receptor agonist and 5-HT2C receptor antagonist, is now marketed as an antidepressant. The potential interactions of several of the targets mentioned above will be discussed. Acknowledgements: The authors are grateful to the Canadian Institutes of Health Research (CIHR), the Canada Research Chairs program and the University of Alberta for Funding. Key words: Antidepressants, biogenic amines, GABA, glutamate, HPA axis, CRH, substance P, neuroactive steroids, glia

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S50-1

SYMPOSIA

[PS-01] Symposium Title: Epigenetics or genetics: Gene-environment interactions over the life - span Alzheimer’s disease: Genes and/or life style

Engin Eker

Istanbul University, Cerrahpaşa School of Medicine, Department of Psychiatry E-mail: [email protected]

A number of genetic risk factors have been identified, but only a small proportion of Alzheimer’s disease (AD) cases can be explained by specific gene mutations. Several genetic risk factors have been linked to AD. Mutations in APP, PS1, and PS2 genes have consistently been associated with early-onset familial Alzheimer’s disease (FAD). A majority of AD cases manifest as sporadic late onset form (LOAD) typically with onset above the age of 65 years. Most people who develop Alzheimer’s are diagnosed after age 80. More recently a large number of genes have been implicated as a risk to LOAD, but only a few of these associations have been replicated such as the gene encoding for the APOE4 allele or loci in the clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and complement receptor1 (CR1). Most diseases of aging are influenced by gene-environment interactions. AD has both genetic and environmental risk factors. The genetic susceptibility influenced by genes like ApoE4 are factors to be aware of, but perhaps more important are the environmental risk factors. Environmental risk factors can act as triggers in the expression of gene potential. Numerous studies indicate that ApoE4 carriers may be more vulnerable to environmental factors. Recent studies have shown that dietary factors, such as exposure to a Mediterranean diet, fish and high omega-3 diets, cigarette smoking, head trauma, infections, systemic inflammation, and metal exposure can significantly alter an individual’s risk of developing AD. On the other hand psychosocial factors such as education, social network, leisure activities and physical activity, chronic stress, and

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S51 Abstracts of the Invited Speakers depression also seem to be connected to the risk of developing AD. There are some somatic factors that are under the direct influence of environmental exposures, such as blood pressure, obesity, diabetes mellitus, cardio- and cerebrovascular diseases, and hyperlipidemia, have additionally been implicated in AD etiology. Key words: Alzheimer’s disease, genes, environmental risk

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S51-2

[PS-02] Symposium Title: Behavioral addictions and treatments: Review of recent data From Don Juanism and nymphomania to hypersexual disorders

Sultan Doğan

Namik Kemal University, School of Medicine, Department of Psychiatry E-mail: [email protected]

Hypersexual Disorder is proposed as a new psychiatric disorder for consideration in the sexual disorders section of the DSM-V. Historically, excessive sexual behaviors were clinically documented by diverse clinicians such as the 19th century Western European pioneer sexologists Richard von Krafft-Ebing (1840–1902), Havelock Ellis (1859–1939), and Magnus Hirshfeld (1868–1935). Benjamin Rush(1745–1813), a physician and founding father of the United States (Rush, 1746-1813) also studied the same subject. These clinicians and investigators described a frame of persistent socially deviant sexual behaviors as well as clinical examples of males and females whose nonparaphilic (i.e., normophilic) sexual appetite was excessive and maladaptive. The clinical examples of such appetitive behaviors described by these investigators were precursors to the 20th century characterization of protracted promiscuity as Don Juanism (Stoller, 1975) or satyriasis (Allen, 1969) in males and nymphomania (Ellis & Sagarin, 1965) in females. The DSM-II (American Psychiatric Association, 1968) recognized sexual deviations as personality disorders but there was no mention of excessive or maladaptive nonparaphilic sexual behavior disorders. By 1980, the DSM-III (American Psychiatric Association, 1980) classified paraphilic disorders as distinct pathologies (Psychosexual Disorders) and a residual diagnostic category, Psychosexual Disorder Not Otherwise Specified included ‘‘distress about a pattern of repeated sexual conquests with a succession of individuals who exist only as things to be used (Don Juanism and nymphomania)’’. In the DSM-IV (American Psychiatric Association, 1994) and its text revision, DSM-IV-TR (American Psychiatric Association, 2000), the original DSM-III characterization of these behaviors was reestablished. Sexual Disorders Not Otherwise Specified (302.9) included a condition characterized by: ‘‘distress about a pattern of repeated sexual relationships involving a succession of lovers who are experienced by the individual only as things to be used’’. Until recently, authors have used different terms for hypersexual disorders, such as “sexual addiction” (Carnes), “paraphilia-related disorders and non-paraphilic hypersexuality” (Kafka), “excessive sexual desire disorders” (Marshal), “problematic hypersexuality” (Finlayson) and “compulsive sexual bahavior” (Cooper and Coleman). These disorders were described as markedly increased expressions of culturally normative sexual desire (fantasies, urges, and behaviors) persisting for a minimum duration of 6 months and associated with clinically significant personal distress, impairment in reciprocal romantic relationships or other adverse psychosocial consequences. Thera are several form of hypersexual disorders such as compulsive masturbation, pornography dependence, telephone sex dependence, cybersex, severe sexual desire incompatibility, anonymous sex and multiple sexual partners (Coleman 1995, Carnes 2007, Kafka 2000, Kafka 2007, Cooper 2002, Cooper 2003). There are significant gaps in the current scientific knowledge base regarding the clinical course, developmental risk factors, family history, neurobiology, and neuropsychology of hypersexual disorder. As is true of so many psychiatric disorders, the comment that ‘‘more research is needed’’ is certainly applicable to these conditions. Although there are significant shortcomings in the state of our current empirical knowledge, there is little doubt that patients with such conditions commonly present to clinicians as well as to specialized treatment programs. Key words: Don Juanism, nymphomania, hypersexual disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S52

S52 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Pathological gambling: review of recent data

Ömer Şenormancı

Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, İstanbul, Turkey E-mail: [email protected]

Gambling, which could also be defined as risking one’s chances for a possible outcome, is a cultural phenomenon as old as humanity. While gambling is a form of entertainment without any drawbacks for the great majority, pathological gambling develops in a small minority. The prevalence (0.2%- 5.3%) in the adult population is gradually increasing due to the ease of accessibility such as Internet gambling. This increase and the accessibility of gambling becoming easier, have led to some sociodemographic changes in the population who have trouble with gambling. Recent studies have shown pathological gambling to be higher in the psychiatric patient population compared to the normal population (with no assigned psychiatric diagnosis) and that it is necessary to be included as part of the questioning in a psychiatric evaluation. Some drugs once thought to be a new hope in the pharmacological treatment of pathological gambling, have been proven ineffective in recent randomized, double-blind, and placebo-controlled studies. Current studies are testing GABAergic and antiglutamatergic drugs, that are thought to be effective in chemical and behavioral addictions, in the treatment of pathological gambling. Two large meta-analysis studies have reported that non-pharmacological therapy approaches are more effective in the treatment of pathological gambling. Behavioral therapy, cognitive behavioral therapy and short, motivational, individualized approaches are demonstrated to be effective. Although it is suggested that behaviorial therapy + cognitive behavioral therapy and short, motivational, and individualized approaches are equally effective, combining the two may improve the efficacy of the treatment. This presentation aims to describe pathological gambling accompanied by contemporary information with respect to treatment. Key words: Pathological gambling, impulse control disorder, pharmacotherapy, psychotherapy

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S53

Is binge eating a type of addiction?

Fulya Maner

Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, İstanbul, Turkey E-mail: [email protected]

Binge eating is characterized by recurrent episodes of eating, in a discrete period of time, an amount of food that is much larger than most people would eat in a similar time period under similar circumstances. There is a sense of lack of control over eating during the episode. Eating is much more rapid than normal and one eats until feeling uncomfortably full. After overeating one feels disgusted, depressed or guilty. Binge eating disorder is included in eating disorders not elsewhere specified in the DSM-IV and is a symptom of bulimia nervosa and anorexia nervosa. Research has shown that patients with eating disorders have high rates of co-occuring substance use disorders. The substance of abuse and food appear to compete for sites in the brain and abstinence from substance use causes craving for the substance and also for food. Addictions involving food and substances share similar etiologies and behavioral symptoms. Individuals suffering from binge eating disorder are more likely to have first degree relatives with a substance abuse disorder. According to retrospective reports of patients, the initiation of disordered eating usually began before substance abuse. The general reward pathway includes the ventral tegmental area and basal forebrain. Substance abuse has been shown to change the neural processes around these connections. The mesolimbic dopamine system connects the ventral tegmental area to the basal forebrain and is critical for the self-administration of psychomotor stimulants. Dopamine deficiency has been suggested to be a common characteristic of individuals who are prone to substance or food addiction. Striatal dopamine receptor (DRD2) availability is significantly lower in obese individuals than in controls. Body mass index is shown to correlate inversely with measures of D2 receptors. Functional neuroimaging studies have revealed that pleasant smelling, looking, and tasting food has reinforcing characteristics similar to drugs of abuse. Many of the brain changes reported for hedonistic eating are also seen in various types of addiction. Overeating may have an acquired drive similar to drug addiction with respect to motivation and incentive craving. In both cases, the desire and continued satisfaction occur after early and repeated exposure to stimuli. Addictive behavior manifests itself in permanent preoccupation with food and eating, withdrawal symptoms, continuation of disturbed

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S53 Abstracts of the Invited Speakers eating behavior in spite of negative consequences, loss of control, and frequent relapse. Human and animal studies have demonstrated that in some brains the consumption of sugar-rich foods or drinks primes the release of euphoric endorphins and dopamine within the nucleus accumbens, in a manner similar to some drugs of abuse. The neurobiological pathways of drug and “sugar addiction” involve similar neural receptors, neurotransmitters, and hedonistic regions in the brain. Craving, tolerance, withdrawal, and sensitization have been documented in both human and animal studies. In addition, there appears to be cross sensitization between sugar addiction and narcotic dependence in some individuals There also appears to be some common genetic markers between alcohol dependence, bulimia, and obesity, such as the A1 allele gene and the dopamine 2 receptor gene. Key words: Binge eating, eating disorder, addiction

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S53-4

[PS-03] Symposium Title: Painful syndromes in psychiatry and their managements Pain and personality

Mehmet Ak

Department of Psychiatry, Gulhane School of Medicine, Ankara, Turkey E-mail: [email protected]

There is a dynamic two-way interaction between pain and personality and the psychophysiology and anatomy of this relationship are not elucidated fully. Is there a specific personality type of pain or do some people perceive and express pain more than others? Probably there is no clear answer to this question. So far chronic pain has been shown to affect personality, as indicated by studies using Cloninger’s Temperament and Character Inventory. A relationship has been demonstrated between some personality traits and pain. In studies that reported the prevalence of personality disorders, associations with chronic pain vary between 31% to 81%. The most frequently identified personality trait is one with paranoid features. Today I will talk mainly about studies using Cloninger’s model, because Cloninger’s integrative psychobiological approach provides a flexible framework for both clinical assessment and treatment planning. The most significant and consistent result of these studies was elevated harm avoidance scores. Harm avoidance scores still remain high even after controlling for the effect of depression and anxiety. Thus this temperament dimension is possibly an important state and trait feature for development of psychosomatic illnesses. These findings also confirmed that serotonergic systems are involved in the process of psychosomatic organization. Cloninger described that people with chronic anxiety, avoid harm that is characterized by more pain, are difficult to calm, tire easily, and display specific signs based on specific anticipatory anxiety. Harm avoidance refers to an inherited tendency to block the behavior in the answers given to the blocking, non-rewarding, and punishment signals. High harm avoidance behavior is observed in the form of social withdrawal, becoming tired easily, staying away from strangers, fear of uncertainty, and being pessimistic that there would be some problems in a situation even when others do not worry.. These people are timid, passive, insecure, and pessimistic individuals. Looking at the size of the character, it is seen that low self-directedness scores are the most common finding. The original meaning of self-directedness is in accordance with choosing goals and values of the individual, optimization of the behavior to maintain a situation, editing capabilities, and being strong-willed. Individuals with low self-directedness do not expect to be able to control and positively influence an aversive situation and overcome obstacles. Self-directedness is closely related to the concept of self-efficacy. Self-efficacy is defined as the personal conviction that one can successfully show problem-solving behavior in a given situation. There is much evidence which suggests that low self-efficacy plays an important role in pain control, coping with disability, and treatment outcome. Our clinical experiences show that pain can sometimes be the symbol of help, sometimes the quest for attention, and other times problems that can not be expressed. Emotions that are not expressed can mean pain and unexpressed emotions can be the cause of pain for some people that do not heal. In order to understand and to treat these people, employing a holistic assessment and approach are very important. Key words: Character, pain, temperament

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S54

S54 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

The differences between SSRIs and SNRIs in the treatment of psychiatric pain syndromes

Abdurrahman Altındağ, Gülçin Elboğa

Gaziantep University, Medical School, Department of Psychiatry, Gaziantep, Turkey E-mail: [email protected], [email protected]

The occurrence of depression with physical symptoms and pain is common. On the other hand, comorbid depression is also common in chronic pain syndromes. Antidepressants are effective in the treatment of psychological and physical symptoms of depression and chronic pain symptoms of non-depressed patients. It is not well described how antidepressants relieve the pain. However, it is suggested that this effect is related to serotonin and noradrenaline. Analgesic effects of antidepressants are independent from their effects on the mood. Antidepressants which have effects on both serotonin and noradrenaline are more effective than those with effects on one of these neurotransmitters in the treatment of depression and comorbid pain syndromes. Tricylic antidepressants (TCAs) have serotoninergic and noradrenergic effects. Therefore, they are superior to monoaminergic antidepressants, such as SSRIs, with regard to analgesic and antidepressant effects. The usage of TCAs is limited because of their safety profile and side effects. SNRIs have similar analgesic effects to TCAs. On the other hand they have lower side effects and a better safety profile. Additionally, SNRIs are more effective than SSRIs in the treatment of physical pain syndromes. SNRIs have a similar safety profile to SSRIs and almost similar costs to the older agents. Better diagnosis and treatment of pain symptoms, which are strong indicator of depressive relapses, will provide better quality of life and productivity in patients with depressive disorders. Key words: SSRI, SNRI, pain

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S55

How does alexithymia lead to painful syndromes?

Hüseyin Güleç

Erenkoy Psychiatry Hospital, Istanbul, Turkey E-mail: [email protected]

Several studies have focussed on defining the network of brain structures involved in pain. Pain perception (sensory discriminative, affective/emotional, cognitive/evaluative) has been shown to depend on different areas of the brain. Modern neuroimaging methods have been used to determine whether different pain symptoms involve similar brain structures. These studies indicated that acute physiological pain and neuropathic pain have distinct although overlapping brain activation patterns, but that there is no unique pain matrix/allodynia network. Several contemporary neuroscientists and cognitive scientists make a similar distinction between emotions as bodily events and feelings as mental events and regard symbolization as an important element in the cognitive processing of emotions. Awareness of feelings, together with the thoughts, fantasies, and memories that they elicit, facilitates modulation of the emotional arousal induced by stressful events. Feelings are attributed to the symbolic representation in working memory of the activity of unconsciously operating subsymbolic systems that generate the brain states and bodily responses which comprise emotions. These representations become integrated with representations of past experiences and representations of the self. Attributing the feeling of specific basic emotions to ‘viscerosomatic self-representations’ in the lower levels of the brain, attributing reflective awareness and the capacity for experiencing higher-order feelings to linguistic symbolizations and an ability to think in perceptual images is important for the parsing and regulation of emotional states. According to Lumley alexithymia is associated with tonic physiological hyperarousal, certain types of unhealthy behavior, and a biased perception and reporting of somatic sensations and symptoms. Alexithymia probably influences illness behavior, but there is little support for the hypothesis that alexithymia leads to chronic organic disease. Alexithymia links with physical illness due to four possible pathways: a) alexithymia leads to organic disease through physiological or behavioral mechanisms, b) alexithymia leads to illness behavior through cognitive or social mechanisms, c) physical illness leads to alexithymia, and d) both alexithymia and physical illness result from sociocultural or biological factors. Research on the effects of emotional trauma resulted in the hypothesis that traumatic experiences in childhood or adult life may have adverse consequences for physical health. It has been shown that there is evidence of a correlational association between childhood trauma and somatization in adulthood, and several retrospective studies with very large samples have

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S55 Abstracts of the Invited Speakers demonstrated an association between childhood trauma and the development of somatic disease in adult life. An unanswered question is: what are the psychological/biological mechanisms that might render trauma in earlier years a risk factor for the development of disease later in life? The associations between alexithymia, somatization, dissociation and trauma, have led to the suggestion that dissociation acts as a defense against emotionally distressing memories that are associated with the traumatic avents. Attachment insecurity and associated deficits in affect development and affect regulation are linked not only to the experience of being raised by parents with impaired capacities for mentalization, but sometimes also to more severe developmental traumas. Dissociation within emotion schemas is initially an adaptive response to external danger arousal and is especially severe when the child experiences the parent as a threat, for then there is no safe place to be. Key words: Alexithymia, cognitive processing of emotions, trauma, attachment, mentalizing, somatization

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S55-6

Hypnotherapy for painful syndromes in psychiatry

Kerem M. Doksat

MD, Professor of Psychiatry, POLIMED Psychiatric Center E-mail: [email protected], [email protected], [email protected]

Hypnosis is a misnomer first used by Scottish Surgeon James Braid for a phenomenon probably as ancient as mammalian history. After the Austrian Neuropsychiatrist Sigmund Freud has fouled hypnosis in order to glorify his own theory, especially American Psychiatrist Milton Hyland Erickson rebuilt the reputation of hypnosis (1). In 1846, James Esdaile successfully performed 345 major operations by using mesmeric method in India. English surgeon John Ellitson mentioned similar success in many operations in 1843. With the introduction of ether in 1846 and chloroform in 1847, the mesmeric method, which has already serious oppositions, was forgotten. Hypnosis may be used alone or in combination with other methods. Its use in cancer pain, especially during the terminal phase, may reduce the requirement for opioids, or even totally eliminate them. Hypnosis may help the patients to experience with their consciousness fully open and free from side-effects like grogginess of the opioids during last phase before their terminal coma. It can be used in burns and for pain free labor. In dentistry it can be used for analgesia, dentists’ chair phobia, and getting rid of gag reflex. It is effective in 30 to 50 percent of phantom limb pain cases. Hypnosis is reported to be effective for the treatment of migraine and other headaches and in many other pain syndromes; I also have a lot of anecdotal evidence. The approach should be adjusted for the patient; the skill and experience of the hypnotist, his or her relationship with the patient and the patient’s personal characteristics and preferences must be adjusted according to all of these. Indeed, hypnotic procedures may help people who are not much hypnotizable. For example, in cases experiencing both pain and tension intensively, even induction of relaxation reduces pain and in many of the hypnotic procedures, relaxation is utilized. If the patients cooperate well and accepts the procedure seriously, even if they are not hypnotizable, they may practice the hypnotist’s relaxation suggestions with success while sitting or lying comfortably (2). The principal techniques are (2,3): 1) Direct suggestion, 2) Utterance of neurophysiological metaphors, 3) Glove anesthesia replacement technique, 4) Replacement pain symptom’s site or differentiating the pain symptom, 5) Dissociation by using the imagination, 6) Technique of different interpretation of pain, 7) Auto-hypnosis (self-hypnosis). As a summary, the effect of hypnosis on pain is mediated by two mechanisms: 1) Muscle relaxation, 2) Change in perception and cognitive distraction. Hypnotherapy can be effective in many painful syndromes if suitable patients are chosen. Group psychotherapy and hypnosis can be effective in the treatment of cancer patients’ pain (4).

References: 1. Doksat R. Tatbikatı ve Nazariyatı ile Hipnotizma. İstanbul: Kader Basımevi, 1962. 253-281. 2. Doksat MK. Ağrı ve Psikiyatri. Bursa: Psikiyatri ve Sanat Yayın Evi, 2003. 165-172. 3. Arred Barabasz, Johnn G Watkins Hypnotherapeutic Techniques 2E. New York: Brunner-Routledge. 2005. 219-239. 4. Porter LS, Keefe FJ. Psychosocial issues in cancer pain. Curr Pain Headache Rep. 2011 Aug;15(4):263-70.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S56

S56 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

[PS-04] Symposium Title: Adult attention - deficit hyperactivity disorder (ADHD) and comorbidity ADHD and mood disorders in children

Rasim Somer Diler

Department of Psychiatry, University of Pittsburgh, PA, US E-mail: [email protected]

Five to 40% of children and adolescents with attention deficit hyperactive disorder (ADHD) also have comorbid major depressive disorders (MDD). Moreover, youths with ADHD have up to a 4 times higher risk of developing depressive disorders than the general adolescent population. Comorbidity with MDD has been associated with elevated impairment and higher rates of hospitalization versus ADHD alone. However, depression in youths with ADHD may be more difficult to diagnose, given that some symptoms overlap between the two disorders. Moreover, many of the medications used to treat ADHD cause side effects resembling symptoms of MDD. Available studies suggest the particular importance of anhedonia, social withdrawal, psychomotor retardation, negative views of self and future, and suicidal thoughts as symptoms that distinguish MDD in youths who have ADHD. Despite ongoing controversy, the view that pediatric bipolar disorder (PBD) is rare or non-existent has been increasingly challenged not only by case reports but also by systematic research; however, a significant portion of bipolar youth, especially children, have high comorbidity with ADHD. Significant debate exists on whether early onset bipolar disorder is mistakenly attributed to attention deficit hyperactivity disorder (ADHD), or whether ADHD is frequently misdiagnosed as mania. Among pediatric-onset cases of bipolar disorder, comorbid ADHD is frequently seen, and there is strong evidence to suggest that this pattern has a familial and genetic basis. Differentiating bipolarity in children with ADHD is not an academic discussion but also a great concern because of the associated complication of the treatment of these disorders. It is suggested that manic symptoms should represent a distinct change from a child’s usual level of functioning (e.g., change or worsening of distractibility during a mood episode in children with ADHD). There are some symptoms that mainly occur in BD youth as compared to other disorders (e.g., ADHD) and may help to differentiate between BD and these disorders, such as clinically relevant euphoria, grandiosity, decreased need for sleep, hypersexuality (without history of sexual abuse or exposure to sex), and hallucinations. We need larger longitudinal studies to better understand the risks and resilience factors of developing BP in ADHD youth. Key words: ADHD, depression, bipolar, child

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S57 Academic and occupational problems in ADHD

Mücahit Öztürk

PEDAM Psikiyatri Merkezi, İstanbul, Turkey E-mail: [email protected]

Attention Deficit Hyperactivity Disorder (ADHD) is a syndrome of inattention, hyperactivity, impulsiveness and other deficits of executive functions. It’s now well known that ADHD often continues into adulthood (1, 2). ADHD is a chronic disorder which leads to a negative impact on functioning throughout the life cycle (3). Children with ADHD are at significant risk of multiple forms of adolescent maladjustment. Approximately up to 60% of childhood cases continue symptomatic into adulthood. In the remaining 40 percent symptoms may remit in early adulthood (4). The manifestation of ADHD changes over the course of life. In some cases the hyperactivity may disappear but decreased attention span and impulse control problems persist (5). Approximately 1 in 25 adults have ADHD, 90% of whom may be currently untreated, with a potentially negative impact on the lives of patients and their families (6). Significant legal, academic, social, and occupational problems have been observed in adults with ADHD (7). Follow up studies suggest that up to 33% of ADHD teens versus 1% to 9% of controls drop out high school. Children with ADHD are at risk of negative academic outcomes. ADHD and similar problems entail a risk of underachievement at school. The results indicate that students with ADHD underachieve in the school situation in relation to their optimal cognitive capacity (3). Adolescents with ADHD complete less education by 2-3 years and demonstrate lower occupational performance at the age of 25 years. Adults with ADHD may struggle with frequent job changes, frequent partner changes, higher rates of divorce, increased motor vehicle accidents, poor money management and higher rates of unwed pregnancy (8). Although their educational performance is lower than people without ADHD, their early employment histories don’t differ from those people with similar education (5). Adolescents with ADHD were more likely to smoke cigarettes and use illicit drugs. Their academic attainment was below age norms with more than one fourth repeating grades (9).

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S57 Abstracts of the Invited Speakers

Studies show that effective treatment significantly improves quality of life (3). Severity of childhood ADHD and treatment significantly predict the persistence of ADHD into adulthood (5). As previously shown by some research for children and adolescents, stimulant medications alone did not eliminate the academic achievement deficit of ADHD undergraduates. ADHD patients who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated. Adolescents with ADHD were also significantly more likely to be absent during the academic year, and they were over eight times more likely than adolescents without ADHD to drop out of high school. These findings demonstrate that children with ADHD continue to experience severe academic impairment into high school (10). Key words: Attention deficit hyperactivity, academic performance, occupation

References: 1. Barkley RA. Major life activity and health outcomes associated with attention-deficit / hyperactivity disorder. J. Clin Psychiatry 2002;63 12:10-15. 2. Weiss G, Hechtman L. Hyperactive Children Grown Up: ADHD in Children, Adolescents, and Adults. New York, NY: Guilford Press; 1993 3. Cheng K, Myers KM, Stubble DE. Attention deficit hyperactivity disorder Child and Adolescent Psychiatry The Essentials Lippincott Williams &Wilkins 4. Biederman J, Mick E, Faraone SV. Age dependent decline of symptoms of attention deficit hyperactivity disorder: Impact of remission definition and symptoms type. Am J Psychiatry 2000 157:816-818 5. Sadock BJ, Sadock VA. Textbook of Child and Adolescent Psychiatry. 2009 Lippincott Williams &Wilkins 6. Culpaper L, Mattingly G. Challenges in Identifying and Managing Attention-Deficit/Hyperactivity Disorder in Adults in the Primary Care Setting: A Review of the Literature Prim Care Companion J Clin Psychiatry 2010 v. 12(6); 7. McCann BS, Roy-Byrne P Attention-deficit/hyperactivity disorder and learning disabilities in adults. Semin Clin Neuropsychiatry. 2000 Jul;5(3):191-7. 8. Spetie L, Arnold EL. Attention deficit hyperactivity disorder in Lewis Child and Adolescent Psychiatry A Comprehensive Textbook 2007 Lippincott Williams &Wilkins 9. Lam AK, Ho TP Early adolescent outcome of attention-deficit hyperactivity disorder in a Chinese population: 5-year follow-up study. J Fam Pract. 2011 Jun;60(6):364-7. 10. Kent KM, Pelham WE Jr, Molina BS, Sibley MH, Waschbusch DA, Yu J, Gnagy EM, Biswas A, Babinski DE, Karch KM.The academic experience of male high school students with ADHD.Pediatrics. 2009 Jul;124(1):71-8.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S57-8

[PS-05] Symposium Title: Brain mapping, TMS, NVS, biofeedback and deep brain stimulation in treatment of psychiatric disorders Concomitant use of qEEG and rTMS in treatment of depressive disorder, new approaches

Nevzat Tarhan, Gökben Hızlı, Serap Aydın

Üsküdar University, Neuropsychiatry Istanbul Hospital, Istanbul, Turkey E-mail: [email protected], [email protected]

Repetitive transcranial magnetic stimulation (rTMS) therapy has been approved for treatment of depression by the FDA in 2008, and was included in APA Guidelines as published in October, 2010 issue of American Journal of Psychiatry. Although its efficacy is not as high as the efficacy of ECT, rTMS is safer in the treatment of depression in older patients. Especially the absence of common treatment side effects of ECT, such as confusion and memory problems, makes rTMS treatment more valuable in patients with high side effect risk. This study was performed by the quantitative EEG (qEEG) monitoring before and after rTMS treatment. The aim was to examine the predictive value of qEEG as a biological indicator of response to rTMS treatment. In Neuropsychiatry Istanbul Hospital, between dates of 2006-2010, rTMS had been applied to 1283 patients with a diagnosis of treatment- resistant depressive disorder. The patients discontinued the psychotropic medications 12 hours before the qEEG monitoring. qEEG records were taken just before the first and the last rTMS sessions. HAM-D 17 was performed before and after 15-20 (mean was 18) sessions of rTMS treatment. The patients with a medical history of epilepsy were excluded. The cases with no history of seizures, but with suspicious epileptical abnormality in pre-treatment EEG were included with special medical caution. rTMS treatment was performed at left DLPFC, as 25 hz. and 1000 pulse, one session on each day, a total of 15-20 sessions, with Magstim Rapid. From 1283 cases, one patient had epileptic seizure as an adverse effect. Due to contraction of facial muscles, one patient had a broken tooth. In 3 patients suffering from tinnitus occurred, but later tinnitus decreased significantly. The statistical analyses of the cases are ongoing. The initial results with remission and response rates will be presented. qEEG power spectrum changes and changes in the activation compared to normative data base in LORETA will be evaluated. Key words: Repetitive transcranial magnetic stimulation (rTMS) therapy, quantitative EEG, depression treatment

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S58

S58 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

What does transcranial magnetic stimulation (TMS) promise in psychiatric disorders other than depression? Future perspectives

Bahadır Bakım

Sisli Etfal Research and Teaching Hospital, Psychiatry Clinic, Istanbul, Turkey E-mail: [email protected]

Up to 40% of OCD patients fail to respond satisfactorily to generally adequate treatment options, and 10% cannot be helped at all. Because OCD may be related to increased neural activity in prefrontal subcortical circuits, the inhibitory effect of rTMS was hypothesized to be beneficial in OCD treatment. rTMS has recently demonstrated remote effects, with left prefrontal stimulation inducing changes in cerebral perfusion in the bilateral anterior cingulate and orbitofrontal cortex. In conclusion, in open-label studies, high-frequency rTMS of the right and/or left DLPFC appears to be effective in reducing obsessive-compulsive symptoms. However, this could not be replicated in double-blind, sham-controlled studies. As the efficacy of rTMS is often time limited, the necessity of a second rTMS after several weeks should be investigated and functional MRI studies of rTMS in OCD are needed to clarify the specific stimulation region of rTMS. Otherwise, as the improvement of symptoms is often noted in sham settings, it would be interesting to investigate the neural underpinnings of the placebo effect caused by sham rTMS. Several initial studies on negative symptoms of schizophrenia have suggested that the condition seems to respond to high frequency (20 Hz, 10 Hz) repetitive transcranial magnetic stimulation (rTMS). Low frequency rTMS ( <= 1 Hz) inhibits cortical excitability and leads to a weakening of the transfer at the synapses. Some authors documented the superiority of 10 Hz rTMS using a sham-controlled parallel design (110% of motor threshold, over left dorsolateral prefrontal cortex), and found a statistically significant improvement in negative symptoms of schizophrenia patients. Interestingly, in this study, positive symptoms deteriorated from baseline. However, in another recent study with a similar controlled design, some authors failed to find significant improvement. Positive symptoms, as globally assessed by PANSS-P, do not show a statistically significant improvement after rTMS but a marked and significant improvement in severity of auditory hallucinations is obtained. More studies need to be conducted for further investigation of the effects of short term and prolonged application of TMS on negative and positive symptoms in schizophrenia. TMS has also been applied to study motor cortex changes in patients with cognitive disorders such as AD, frontotemporal dementia, and dementia with Lewy bodies. Further investigations with larger sample sizes are needed to identify MCI and AD subjects and separate them from the healthy population, and to identify connectivity changes occurring during the development of AD. Active rTMS with exposure may have symptomatic and physiological effects. Larger studies are needed to confirm and verify whether rTMS plus exposure therapy has a role in the treatment of PTSD. Some authors reported antimanic effects from rapid transcranial magnetic stimulation of the right prefrontal cortex. Further systematic studies are needed. The prefrontal cortex may be a promising TMS target for reducing pain in neuropathic, rheumatologic and post-surgical populations although the mechanisms by which it might work remain unclear. Future studies are needed to determine TMS treatment parameters and cortical targets that can optimize its effects and duration. Key words: TMS, OCD, bipolar disorder, PTSD, schizophrenia, neuropathic pain

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S59 Transcranial magnetic stimulation (TMS) as a treatment for depression

Ayhan Algül

Department of Psychiatry, GATA Haydarpasa Training Hospital, Istanbul, Turkey E-mail: [email protected]

Transcranial magnetic stimulation (TMS) is a noninvasive method of brain stimulation in which magnetic fields are used to induce electric currents in the cerebral cortex, thereby depolarizing neurons. TMS based on focal electromagnetic induction, was introduced in 1985 by Anthony Barker (1). Both repetitive TMS (rTMS) and electroconvulsive therapy (ECT) use electrical energy to induce neuropsychiatric change; however, the magnetic fields in TMS are unaffected by the high impedance of the skull and thus, TMS can be applied relatively with no pain to conscious patients without the need for sedation. TMS/rTMS is found to be a promising noninvasive treatment for various neuropsychiatric conditions. Therapeutic utility of TMS has been reported in the literature for psychiatric disorders, such as depression, acute mania, bipolar disorders, panic, hallucinations, obsessions/compulsions, schizophrenia, catatonia, post-traumatic stress disorder, or drug craving. Single-pulse TMS was first used as a possible therapeutic tool for depression in 1993. Since then, depression continues to be the most commonly studied psychiatric condition in the application of rTMS (2). Most studies have suggested that the active rTMS treatment has greater antidepressant efficacy than sham stimulation (3). A number of clinics have been set up offering TMS for treatment of various diseases worldwide and rTMS is already approved by some countries for treatment of depression (i.e., Canada and Israel). In 2008, rTMS was approved by the Food and Drug Administration in the United States for the treatment

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S59 Abstracts of the Invited Speakers of patients with medication-refractory unipolar depression who have failed one good (but not more than one) pharmacological trial. Key words: Transcranial magnetic stimulation, depression, rTMS

References: 1. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet1985;1(8437):1106-7. 2. Nivoli AM, Colom F, Murru A, Pacchiarotti I, Castro-Loli P, González-Pinto A, et al. New treatment guidelines for acute bipolar depression: A systematic review. J Affect Disord 2011; 129(1-3):14-26. 3. Fitzgerald PB, Hoy K, McQueen S, Maller JJ, Herring S, Segrave R, et al. A Randomized Trial of rTMS Targeted with MRI Based Neuro-Navigation in Treatment- Resistant Depression. Neuropsychopharmacology 2009; 34(5):1255-62.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S59-60 Vagus Nerve Stimulation (VNS) in depression treatment

Şadiye Visal Buturak

Department of Psychiatry, Kırıkkale University, Faculty of Medicine, Kırıkkale, Turkey E-mail: [email protected]

Major Depressive Disorder (MDD) is a prevalent, chronic, recurrent and disabling disorder and it is predicted that MDD will be the second most common cause of incapacitating disease in 2020 (1). Although a broad range of effective treatments is available, a considerable proportion of patients do not respond adequately (2). Patients who have already experienced recurrent depressive episodes often relapse and do not achieve full remission despite treatment with conventional therapies (3). A need for the development of alternative treatments for treatment resistant depression (TRD) that are effective, have fewer side-effects or have longer-lasting antidepressant effects has been identified. Vagus nerve stimulation (VNS) therapy is a type of treatment where a small electrical pulse is administered through an implanted neurostimulator to a bipolar lead attached to the left vagus nerve (4). VNS was approved by the US Food and Drug Administration in 2005 for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years or older who are experiencing a major depressive episode (MDE) and have not had an adequate response to 4 or more adequate antidepressant treatments. The mechanism of action of VNS is not fully understood although emerging data suggest that VNS therapy modulates the function of neural structures implicated in depression and also influences monoaminergic neurotransmission (5). In a randomized sham-controlled trial, VNS only showed a response rate of 15.2% compared to 10% with sham treatment (p=0.251) during a 10 week trial (6). But most of the open-label studies about the short and long-term efficacy of the VNS in patients with TRD showed significant reductions in response and remission rates. Rush et al. examined the effect of VNS in adult outpatients with nonpsychotic, treatment-resistant major depressive or bipolar I or II (depressed phase) disorders. Response rates were 40% for the Hamilton Depression Rating Scale (HDRS) (7). In an open pilot study of VNS in outpatients with treatment-resistant MDEs the response rate was 30.5% for the primary HDRS (28) measure, after 10 weeks of VNS (p =.0057) (8). George et al. compared data from the 205 patients who completed the 12-month naturalistic study that was done by Rush et al. (9) with a matched control group of 124 patients with TRD who received only treatment as usual (TAU). Response rates according to the HDRS (24) at 12 months were 27% for VNS+TAU and 13% for TAU (p <.011) (10). In an open, uncontrolled multi-centre study of VNS therapy as an addition to stable pharmacotherapy, the response and remission rates were found to be 37% and 17% after 3 months of VNS and 53% and 33% after 1 year of VNS, respectively (11). The most common side effects due to the VNS were incision pain, voice alteration, neck pain, headache, cough, dysphagia and dyspnoea. Although it has a good safety profile, the present evidence supporting its use is still limited. VNS seems to be an interesting new approach to treating TRD. However, despite the promising results reported mainly in open studies, further clinical trials are needed to confirm its efficacy in major depression and to understand its mechanism of action. Key words: Depression, vagus nerve stimulation

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S60 Neurophysical basis of neurostimulative psychosurgery: A historical review, new perspectives, and future insights

Mehmet Dumlu Aydın

Department of Neurosurgery, Medical Faculty of Ataturk University, Erzurum, Turkey E-mail: [email protected]

Psychosurgery most likely began with burr holes in skulls for mystical causes over a millennium ago. Modern psychosurgery is concerned

S60 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers with the determination of disordered brain structures at the levels of neurons and neuronal populations in brain mapping by creating mathematical formulations and treatment. Psychosurgery aims to regain systematic and comprehensive brain functions via minimally invasive nondestructive neurosurgical applications. Psychosurgery is indicated for treatment-refractory major mental illnesses such as depression, obsessive compulsive disorder, schizophrenia and others. Neurostimulative methods are preferred to neuroablative methods. Neurons have highly complex morphological, electrophysiological, and biochemical properties as reflected in many psychomotor functions, continuation of mental homeostasis, repertoire of activity patterns and multiple signaling pathways. Morphologically, neurochemically and electrophysiologically heterogeneous neuron groups project to the cerebral cortex, deep brain structures, brain stem, spinal cord and autonomous ganglia. These highly complex ascending and descending pathways participate in different functions, including cognition, motivation, emotion, speech, calculation, memory and autonomic regulation. Disorders of neuronal populations can cause neuropsychiatric illnesses. Neurostimulative applications are the most useful treatment methods for intractable cases. However, in experimental studies, stem cells and teacher neurons specifically educated by computerised mediums have begun to be implantated into the brain for education and stimulation of dysfunctional neuron groups. Psychosurgery has been directed to neurocomputer interfacing technologies. Hybride neuroelectric devices, neuromimetic protheses, sonic and photonic multichip modules, biotic-abiotic neuromodulators, bio-robotics and reconfigurable neural nanodevices have shown promise for future excellent treatment strategies for mental illnesses. Key words: Psychosurgery, deep brain stimulation

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S60-1

[PS-06] Symposium Title: Neuroimaging in psychopharmacology: An update What is the real meaning of ventricular enlargement in schizophrenia?

Nazlı Buğçe Vedin Özçelik

Department of Psychiatry, Ege University, Izmir, Turkey E-mail: [email protected]

Schizophrenia usually starts during adolescence or young adulthood but tends to persist throughout life. Even at the time that the concept of schizophrenia was first defined, it was thought to be a brain disease. Before the development of brain imaging techniques, post-mortem brain examinations were performed. It was reported that patients had frontal atrophy and less brain weight than the normal population. After the development of computed tomography and magnetic resonance imaging techniques, the number of the studies in this field increased. Structural MRI imaging studies indicated that brain abnormalities were present at the onset of the disease. One strong piece of evidence indicating that schizophrenia is a neurodevelopmental disorder derives from the fact that many types of brain abnormalities are present at the time of the first episode off illness. These include decreased cerebral size, decreased frontal and temporal lobe sizes, decreased thalamic size, decreases in gray matter and white matter volumes and enlargement of the ventricles. These findings support the likelihood that this illness arises because of aberrations in the complex neurodevelopmantal processes that modulate brain maturation during the adolescent and young adult period. Lateral ventricular enlargement is one of the most consistent findings in patients with schizophrenia. However whether progressive ventricular dilatation occurs during the course of the illness has been controversial. Some findings suggest that there is progressive ventricular enlargement with no significant effect of age of onset, duration of illness or age at the baseline scan. In some longitudinal studies there was evidence that negative symptoms have an association with increases in total CSF volume and in the ventricles as indicated by the ventricular–brain ratio. Patients who achieve longer periods of remission have less expansion of the CSF, although, some findings support the premise that there is a subgroup of patients with neuroprogression. Key words: Schizophrenia, magnetic resonance imaging, lateral ventricle

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S61

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S61 Abstracts of the Invited Speakers

Neuroimaging studies in dementia, psychiatric disorders, drug discovery, and more

Devrim Ünay

Department of Electrical-Electronics Engineering, Bahcesehir University, Istanbul, Turkey E-mail: [email protected]

The continuous progress achieved in medical imaging technology in the past decades has led to considerable improvement in patient care. In consequence of this progress, neuroimaging (imaging the structure or function of the brain) has gained an increasingly important role in research and clinical practice. Dementia, a psychiatric/mental disorder defined as progressive loss in cognitive skills such as learning, memory, orientation and language, is a devastating and irreversible brain syndrome. Due to its increasing prevalence (especially in aging populations), long duration, caregiver burden and high financial cost of care, dementia has emerged as one of our major public health problems affecting 20% of those over 80 years of age. As a result there is an increasing demand for a more accurate and earlier diagnosis and the value of neuroimaging in improving the diagnostic process is becoming widely accepted. Neuroimaging assessments may aid in the diagnosis of neurodegeneration as opposed to healthy aging, improve differential diagnosis, assist in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder, improve the tracking of disease progression and finally may serve as an outcome measure for assessing drug efficacy. Hence, in clinical settings the diagnosis of dementia is increasingly taken based on combined analysis of data such as the patient’s cognitive skills, demographic status, family history of dementia and neuroimaging findings (such as the degree and distribution of atrophy). In addition to the improvement in patient care, recent advances in neuroimaging technology also have increased the need for tools to analyze and interpret the growing amount of neuroimaging data acquired. Accordingly, various semi-/fully automatic tools for analysis and interpretation of such data are made available by research centers as well as medical imaging companies. In view of the above, this work aims to provide a non-exhaustive summary of neuroimaging studies in psychiatric disorders with special emphasis on dementia and drug discovery. State of the art studies employing both structural (CT, MRI, etc.) and functional (fMRI, PET, SPECT, etc.) neuroimaging techniques and their potential contribution to diagnostic research as well as to drug discovery will be discussed. The work will also include a brief introduction on the related advances and open questions from an image processing standpoint, and finally present our recent research effort on computer-based measurement of dementia-related neuroimaging findings as compared with experts’ visual assessments for improved disease understanding, diagnosis, prognosis, and therapy planning. Key words: Dementia, drug discovery, fMRI, MRI, neuroimaging, PET, psychiatric disorders, SPECT

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S62

[PS-07] Symposium Title: The rationale of antipsychotic combinations in schizophrenia: Epidemiological and clinical evidences Pharmacogenetics and antipsychotic combinations

Filiz Karadağ

Pamukkale University Medical Faculty, Psychiatry Department, Denizli, Turkey E-mail: [email protected]

Pharmacogenetic studies in schizophrenia aim to use genetic information as a guide to establish individualized treatment options and to optimize the effectiveness of treatment. The heterogeneity of response to antipsychotics results in polypharmacy along and combination therapy into clinical practice, which lead to an increase in drug-related side effects and non-adherence to treatment. Dopamine and serotonin systems may provide some of the genetic polymorphisms and have been proposed to predict the efficacity of antipsychotic drugs. Affecting the intensity of the D2 receptors in the striatum, the DRD2- 141C Ins/Del polymorphism has been associated with unresponsiveness to clozapine in treatment-resistant patients and a longer response time to olanzapine and risperidone in first-episode patients. The D3 receptor DRD3 Ser9Gly polymorphism has been associated with unresponsiveness to clozapine and good response to first generation antipsychotics. The 5-HT2A receptor gene HTR2A-A-1438G and T102C polymorphisms may cause lower promoter activities and decreased 2A receptor density in some brain regions. A-1438G G/G carriers have been found to be less likely to respond to clozapine, olanzapine, and aripiprazole.

S62 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

The T102C SNP C/C genotype has been associated with no response to clozapine and good response to risperidone and aripiprazole. The long allele of the serotonin transporter gene has been reported to be associated with better response to antidepressants, but there are only a few studieson schizophrenic patients. The effectiveness of pharmacogenetics-based combination therapies in patients unresponsive to treatment has not been studied yet; the DRD2 and DRD3 genes may be candidates for study. Antipsychotic metabolism: The Met/Met genotype of the COMT gene causes a 3- to 4-fold lower enzyme activity. The met allele carriers were more likely to respond to clozapine, especially showing improvement in cognitive functions. This polymorphism, seems to deserve assessment of the effectiveness of combination therapies in dealing with cognitive symptoms. The CYP2D6 enzyme plays an important role in the metabolism of antipsychotic drugs. Individuals carrying duplicate or multiple copies of the CYP2D6 gene are known as ultrarapid metabolizers. In ultrarapid metabolizers, due to the decrease in therapeutic efficacy of antipsychotic drugs, a combination of drugs that are metabolized by the same cytochrome enzyme would not provide further improvement in drug response. Antipsychotic-induced side effects: The DRD2 A2 allele of SNP Taq1A, the DRD3 Ser9 Gly Gly allele genetic polymorphisms related to D2 and D3 receptors, the COMT Val allele and the CYP2D6 gene variants have been reported to be associated with an increased risk of tardive dyskinesia. CYP2D6 poor and intermediate metabolizers may be more sensitive to the extrapyramidal side effects of antipsychotics. The 5HT2C gene (759T SNP) and the leptin gene are the most studied polymorphisms for antipsychotic-induced weight gain. All of the aforementioned polymorphisms may have implications for choice of rational antipsychotic combinations. Pharmaco-genetics-based rational antipsychotic combinations may yield promising results for cytochrome enzyme and COMT genes and the genes associated with side effects in schizophrenia. However, this issue should be supported and confirmed by clinical pharmacogenetics studies. Key words: Pharmacogenetics, schizophrenia, antipsychotics, side effects, dopamine, serotonin, polymorphism

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S62-3

Scientific bases of use of atypical antipsychotics

Ender Taner

Department of Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey E-mail: [email protected]

The predominant hypothesis regarding the pathophysiology of schizophrenia is that it is associated with impaired dopamine neurotransmission. The mesolimbic pathway originates from the midbrain ventral tegmental area and innervates the ventral striatum (nucleus accumbens), olfactory tubercle, and parts of the limbic system. The mesocortical pathway, also originating from the midbrain ventral tegmental area, innervates areas of the frontal cortex and has been implicated in learning and memory. Overactivity of the mesolimbic pathway has been implicated in the development of the positive symptoms of schizophrenia. The negative and some cognitive symptoms have been associated with a reduction of dopamine activity in the mesocortical pathways together with a hypostimulation of dopamine receptors in the prefrontal cortex. There are 2 overall goals of treatment: (1) to reduce the activity of hyperactive pathways mediating psychosis and (2) to increase the activity of hypoactive pathways that seem to mediate negative and cognitive symptoms, while simultaneously preserving the activity of the pathways that regulate motor movement and prolactin secretion. There is also a putative interrelationship between N-methyl-D-aspartate (NMDA) hypofunction and dopamine (DA) dysregulation and these processes may be linked to the pathogenesis of schizophrenia. It has been postulated that NMDA hypofunction in the prefrontal cortex and its connections may result in a pattern of dopamine dysregulation. In the prefrontal area, this pattern consists of a dopamine deficit and a hypostimulation of D1 receptors that are linked to the appearance of negative symptoms and cognitive impairment. However, at the subcortical level, NMDA hypofunction results in dopamine excess, hyperstimulation of D2 receptors, and the appearance of positive symptoms. It has also been suggested that the prefrontal dopamine deficit and the subcortical dopamine excess feed back, in turn, to the NMDA circuitry. In addition there is evidence that the deficit in cortical dopamine may also be linked to the generation of a subcortical dopamine excess. There is a complex modulation of dopamine by different serotonergic receptor systems as well as by nicotinic receptors. These may be additional sites for effects of antipsychotics. This conference tries to underline the current possible scientific basis for the use of atypical antipsychotics. Key words: Atypical antipsychotics, schizophrenia, mechanism of action, scientific basis

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S63

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S63 Abstracts of the Invited Speakers

Is fish oil promising in the treatment of depression during pregnancy and lactation?

Evrim Özkorumak

Karadeniz Technical University, Psychiatry Department, Trabzon, Turkey E-mail: [email protected]

Increasing concerns about neonatal syndromes following antidepressant use in the late phase of pregnancy(1) have caused more hesitation about their use. Although inadequate data about in utero exposure of antidepressants may present risks, the risks of untreated maternal depression must be considered as well. One candidate as an antidepressant is fish oil, in light of its omega-3 constituent. Omega-3 fatty acids are long-chain, polyunsaturated fatty acids found in plant and marine sources and helpful in treating various medical conditions (2). Omega-3 fatty acids may prove to be efficacious in a number of psychiatric disorders. Evidence suggests that omega-3 fatty acids may have beneficial effects in mood disorders, including bothmajor depression and bipolar disorder, schizophrenia and dementia. Furthermore, omega-3 fatty acids may prove to be a safe and efficacious treatment for psychiatric disorders during pregnancy and breastfeeding (2). Major depressive disorder (MDD) is prevalent among women of childbearing age. Approximately 15% of women experience an episode of perinatal depression (PND), antenatally and/or postnatally (3). Because there are increasing concerns about possible adverse effects of antidepressant medication use during pregnancy and in breastfeeding mothers (4), it is important to investigate possible alternative treatments. Main dietary risk factors of postnatal depression are low riboflavin, low folate, low docosahexaenoic acid, low eicosapantaenoic acid, low calcium, low magnesium and low zinc. Oil-rich fish are a rich source of n-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (5). Evidence indicates that these fatty acids may be involved in the synthesis and regulation of brain neurotransmitters (dopamine, monoamine and serotonin), which are thought to be reduced in cases with depressive symptoms (6). More specifically, it is thought that high concentrations of DHA located in non-myelin cell membranes of the central nervous system may help support synaptic transmissions (7). Different human studies were identified investigating dietary and/or supplemental sources of n-3 in relation to the development of postnatal depression. Only two of these trials were randomised controlled trials (8,9). Among others, three studies support the theory that dietary and supplemental sources of n-3 are associated with fewer postnatal depression symptoms (8,10,11) and five studies contest this theory (12,13,14). Key words: Omega-3 fatty acids, depression, perinatal depression

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S64

[PS-08] Symposium Title: Advances in complementary alternative psychotropic drugs: Fish oil (omega-3 fatty acids), vitamine B12, folate ve other add-on therapies in psychiatric disorders Can St. John’s Wort be an alternative treatment for depression?

Çiçek Hocaoğlu

Rize University, Medical School, Department of Psychiatry, Rize, Turkey E-mail: [email protected]

The herb St. John’s Wort (Hypericum perforatum) has been used for centuries to treat a variety of medical illnesses. In certain areas of Europe, St. John’s Wort has been a commonly prescribed treatment for depression. In some countries extracts of the plant Hypericum perforatum L. (popularly called St. John’s Wort) are widely used for treating patients with depressive symptoms. Extracts of the plant Hypericum perforatum have been used in folk medicine for a long time for a range of indications including depressive disorders. Some researchers believe that specific chemical constituents of St. John’s Wort produce changes in depression in a manner similar to that of antidepressant medications, yet this hypothesis is problematic. In addition, studies that support the efficacy of St. John’s Wwort in patients with mild-to-moderate depression have limitations that may affect the accuracy of their conclusions. Studies measuring the effect of St. John’s Wort in major depression have reported conflicting results and need to be reexamined. In patients who meet the criteria for major depression, several recent placebo-controlled trials suggest that the tested hypericum extracts have minimal beneficial effects while other trials suggest that hypericum and standard antidepressants have similar beneficial effects. Preliminary data suggest that hypericum extract is effective in atypical depression based on the reported outcome of an 8-week double-blind, placebo-controlled, randomized

S64 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers trial (positive results in patients with vegetative features of atypical depression, i.e. hyperphagia or hypersomnia). The study supports the beneficial effect of St. John’s Wort in depression with atypical features and the validity of the definition of atypical depression on the basis of reversed vegetative signs. Consequently, St. John’s Wort is considered by some to be an alternative to conventional therapies but, clinicians need to know whether it is an effective and safe treatment for different levels of severity of depression. Current evidence does not support its use and because of potential drug interactions, St. John’s Wort is not a benign treatment. Key words: St. John’s Wort, depression

References: 1. Shelton RC. St John’s wort (Hypericum perforatum) in major depression. J Clin Psychiatry. 2009;70 Suppl 5:23-7. 2. Mannel M, Kuhn U, Schmidt U, Ploch M, Murck H.St. John’s wort extract LI160 for the treatment of depression with atypical features - a double-blind, randomized, and placebo-controlled trial. J Psychiatr Res. 2010 Sep;44(12):760-7. Epub 2010 Feb 23. 3. Kasper S, Gastpar M, Müller WE, Volz HP, Dienel A, Kieser M, Möller HJ. Efficacy of St. John’s wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Eur Arch Psychiatry Clin Neurosci. 2008 Feb;258(1):59-63. Epub 2007 Dec 14. 4. Trautmann-Sponsel RD, Dienel A. Safety of Hypericum extract in mildly to moderately depressed outpatients: a review based on data from three randomized, placebo-controlled trials. Affect Disord. 2004 Oct 15;82(2):303-7. 5. Linde K, Mulrow CD, Berner M, Egger M. St John’s wort for depression. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000448.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S64-5

Complementary medicine alternatives for other psychiatric abnormalities (Like insomnia and pain)

Bülent Bahçeci

Department of Psychiatry, Rize Üniversity, Rize,Turkey E-mail: [email protected]

Complementary and alternative medicine have been used for the treatment of a variety of diseases for a long time. Since the applications of these two branches of medicine have been increasingly spreading globally and have been accompanied by inadequate scientific studies in the literature, the NIH has established the National Centre for Complementary and Alternative Medicine (NCCAM). The aims of the centre are to investigate the safety/reliability and efficacy of complementary and alternative medicine applications, and to integrate those that are scientifically proven to be effective into conventional therapies. All health protection and medical applications/practices outside of conventional medicine are referred to as complementary and alternative medicine (CAM). CAM applications are becoming widespread in Turkey, as well, and are sought by 34-77% of sufferers as the first choice for therapy. Recently CAM, which has found applications in a wide range of areas, has also been used for psychiatric diseases. The use of CAM in the treatment of chronic pain, eating and sleeping abnormalities, alcohol and substance addiction, Alzheimer’s disease and delirium has yielded contradictory results in the national and international literature. Therefore, it has been reported that CAM methods require further evidence-based studies. Taking into consideration the widespread use and popularity of CAM, it is evident that these methods must be investigated further for their side effects, dosages, indications, interactions with other drugs, and standardisations. In addition, the regulations concerning their use must be redrawn and physicians must follow the relevant literature in order to prevent possible harm to their patients before initiating CAM treatments. Key words: Complementary and alternative medicine, psychiatry, education

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S65

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S65 Abstracts of the Invited Speakers

Essential fatty acids in ADHD treatment

İbrahim Durukan

Deparment of Child and Adolescent Psychiatry, Gülhane Military Medical School, Ankara, Turkey E-mail: [email protected]

Attention deficit hyperactivity disorder (ADHD) is characterized by problems with attention, hyperactivity and impulsivity. These problems often severely affect families, relationships and school performance. Although stimulants and atomoxetine are efficacious in many children, these medications can have side effects such as insomnia, decreased appetite, irritability and impaired growth. The etiology of ADHD is generally accepted to be complex and multifactorial. Little progress has been made in elucidating predisposing biological factors. Related contributory factors for ADHD etiology are diet, nutrition and particular abnormalities in the metabolism of the long- chain polyunsaturated fatty acids (LCPUFAs). Essential fatty acids (EFAs) as a complementary or alternative treatment for ADHD have been used as both a primary and an adjunctive treatment in many countries. Humans are unable to synthesize linoleic acid (an omega-6 fatty acid), and a-linolenic acid (ALA), an omega- 3 fatty acid. The main dietary sources of linoleic acid and ALA are vegetable oils and their seeds. Both omega-3 and omega-6 LCPUFAs have critical importance for normal brain development and function. Large amounts of both omega- 6 and omega-3 LCPUFAs are deposited in the central nervous system during fetal life. During infancy, dietary intake of both omega-3 and omega-6 LCPUFAs continues to be essential for neuronal development. LCPUFAs and their derivates work as facilitators of dopamine, serotonin and norepinephrine release, as regulators of gene transcription, as modulators of Na+ -K+ ATPase channel function and as the precursors of pro-inflammatory and anti-inflammatory molecular families. The most abundant LCPUFA in the brain is DHA from the omega- 3 series, which is concentrated at nerve cell synapses and is important for neural cell signalling and neurotransmitter processes. There is increasing evidence that omega-3 LCPUFAs play a part in many neurodevelopmental and psychiatric disorders. ADHD, dyslexia, developmental coordination disorder and autistic spectrum disorder are suggested to be related to the omega-6/omega-3 spectrum of disturbances. Several studies of LCPUFA supplementation in children with ADHD symptoms have been conducted. Open-label EFA trials in ADHD demonstrate that ADHD symptoms are responsive to EFA supplementation. Despite successful open-label trials, randomized controlled trials of EFA in ADHD have generally been unsuccessful in demonstrating treatment effects and some of them even displayed better results for the placebo group. There are three studies with partial positive results but these studies represent a small minority and two of them have several methodological limitations. The side effects of EFA are generally related to the gastrointestinal system and usually include diarrhea, nausea, fishy aftertaste, belching and indigestion. These side effects seem to be mild, transient and infrequent, and also appear in the placebo groups. Current findings from randomized clinical trials of EFA in children with ADHD are not promising. Most randomized trials have clearly demonstrated lack of superiority compared to placebo. Moreover, the studies that showed positive findings did not use children properly diagnosed with ADHD and none of them demonstrated clinical improvement in more than one setting. This delineation does not support the use of EFA supplements as a treatment for children with ADHD. Future studies should be planned to consider methodological issues such as proper ADHD diagnosis, blinded controls, adequate sample size and behavioral assessment in more than one setting. Key words: ADHD, essential fatty acids

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S66

Mechanisms of fish oil (Omega-3 fatty acids), vitamin B12, folate and other add-on treatments in psychiatric disorders

Mehmet Cemal Kaya

Dicle University School of Medicine, Department of Psychiatry, Diyarbakir, Turkey E-mail: [email protected]

The need for new treatments has led several investigators to examine the potential role of omega-3 fatty acids, found in marine and plant sources, in the treatment of psychiatric disorders. Omega-3 fatty acids are associated with normal brain development, neuronal plasticity, and function (1). Cell biology and molecular studies suggest that omega-3 fatty acids modulate membrane fluidity and dopaminergic and serotonergic neurotransmission (2). It has been observed that omega-3 fatty acids have effects on the phospholipid cell membrane and the secondary messenger system similar to mood stabilizing drugs like lithium (3). It has been also demonstrated by recent studies

S66 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers that add-on treatments with omega-3 fatty acids in mood disorders significantly improved the symptoms. Another way to investigate the effects of omega-3 fatty acids is by estimating the regional brain concentrations of various metabolites with proton magnetic resonance spectroscopy (PMRS). In a study that used this method in a population with first-episode psychosis, improvement of the negative symptoms of the patients were observed parallel to the increase in glutathione availability and modulation of the glutamine/glutamate cycle with ethyl-eicosapenthaenoic acid augmentation treatment (4). Post-mortem polyunsaturated fatty acid concentrations in the prefrontal areas of antipsychotic-naive schizophrenia patients were found to be lower than those of schizophrenia patients treated with atypical antipsychotics. Additionally, in an animal study, increases in the omega-3 fatty acid concentration in erythrocytes and prefrontal cortex were observed after long-term treatment with risperidone. One of the earliest reports about the possible psychiatric effects of vitamin B12 deficiency belongs to Langdon in 1905. Vitamin B12 together with folate are essential for conversion of homocysteine to methionine and synthesis of adenosyl-methionine. S-adenosyl- methionine is responsible for methylation in the metabolism of neurotransmitters (5). There are various studies that showed associations of depression, dementia and schizophrenia with deficiencies of folate and vitamin B12. Some studies have focussed on folate rather than vitamin B12 and have suggested a stronger role for folate in depression. Independent from serum levels of folate and vitamin B12, augmention with these vitamins may be beneficial to patients who have predominantly cognitive symptoms, who are resistant to treatment, pregnantor use lithium (6). Consequently, augmentation with omega-3 fatty acids, folate and vitamin B12 may have some clinical benefits in the treatment of some psychiatric disorders. However, mechanisms of their actions still need to be further elucidated. Key words: Omega-3 fatty acids, vitamin B12, folate, psychiatric disorders

References: 1. Bazan NG. Lipid signaling in neural plasticity, brain repair, and neuroprotection. Mol Neurobiol 2005; 32: 89–103 2. Yao JK, Leonard S, Reddy R. Altered glutathione redox state in schizophrenia. Dis Markers 2006; 22: 83–93 3. Frangou S, Lewis M, Wollard J, Simmons A. Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol 2007; 21: 435-439 4. Berger GE, Wood SJ, Wellard RM, Proffitt TM, McConchie M, Amminger GP, Jackson GD, Velakoulis D, Pantelis C, McGorry PD. Ethyl-eicosapentaenoic acid in first- episode psychosis. A 1H-MRS study. Neuropsychopharmacology 2008; 33: 2467-2473 5. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 1996; 54:382-390 6. Lindeman RD, Romero LJ, Koehler KM, Liang HC, LaRue A, Baumgartner RN, Garry PJ. Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: Correlations with cognitive and affective functions. J Am Coll Nutr 2000; 19: 68-76

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[PS-09] Symposium Title: From preclinical studies to clinical practice in anxiety disorders Medical disease and anxiety disorders

Hayriye Elbi

Ege University, School of Medicine, Dept. of Psychiatry, İzmir, Turkey E-mail: [email protected];[email protected];[email protected]

Chronic medical illness causes us to face our vulnerabilities and is a significant risk factor for the development of an anxiety disorder. The vulnerability could be associated with the stress of illness and coping with the limitations of illness. Anxiety disorders may also develop secondary to predisposing biological mechanisms (as in diabetes or thyroid disorders) or may be related to a patient’s specific medications. We need to explore the causes of an anxiety disorder and plan our treatment so that it will not interfere with the medical disease and its treatments. Drug interactions are very important in medical comorbidity cases. Every disorder comes with a new life style and necessity for new adaptations. The uncertainty and barriers to daily life worsen the situation. I will review the anxiety associated with medical diseases and the current treatments for it. Key words: Medical diseases, anxiety disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S67

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S67 Abstracts of the Invited Speakers

Genetic models in anxiety disorders

Nurper Erberk Özen

Department of Psychiatry, Ufuk University, Ankara, Turkey E-mail: [email protected]

Animal models are key to our understanding of many human diseases and psychiatric disorders are no exception. Animal models have provided insight into the neurotransmitter systems and brain circuitry underlying psychiatric illnesses that have enabled the screening of potential psychiatric medications for efficacy and guided the search for new pharmacotherapies. However, modeling complex psychiatric disorders in animals presents distinct challenges. Modeling psychiatric disorders in animals is difficult due to the complexity of human thoughts, emotions, and behavior; the heterogeneity of many psychiatric disorders; and the requirement of self-reporting of internal state for diagnosis. According to the DSM-IV, most psychiatric diagnoses are made when a patient displays a certain number of diagnostic criteria. However, patients with the same diagnosis can differ significantly in specific symptoms, perhaps implying differences in the underlying etiology of their disorders and explaining the heterogeneity of response to pharmacotherapy. Many symptoms are identified by the patient’s report of internal state (e.g., obsessive obtrusive thoughts or ruminations). This leads to questions of how we can best model disorders in animals that are, by definition, both heterogeneous and dependent on report of internal state. Rather than attempting to model a psychiatric disorder in its entirety, most neuroscientists focus on individual aspects or dimensions of a disorder and use physical manifestations and measurable behaviors when modeling a particular aspect. Inferences from experiments with animal models have the potential to impact clinical practice; therefore, stringently validating such models is of utmost importance. The strengths and weaknesses of a model can be conceptualized with different types of validity. Three important types of validity are suggested as predictive, face, and construct validity. In the first one, the animal should display reduced anxiety when treated with anxiolytics (predictive validity). In the second type, the behavioral response of an animal model to a threatening stimulus should be comparable to the response known for humans (face validity). Finally, in the third type of validity, the mechanisms underlying anxiety as well as the psychological causes should be identical (construct validity). In the meantime there is no consensus about which type of validity is superior. Some authors argue that predictive validity is most essential but the others suggest that constructive validity is the most crucial. On the other hand, these three requirements are difficult to achieve in any animal model for each anxiety disorder. Moreover, in the related literature, the term“animal model of anxiety” is used for animals that are altered in their anxiety-related behavior, as well as for test assays conceptualized to assess anxiety-related behavior in animals. Key words: Anxiety disorders, genetic, rat, transgenic

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S68

Anxiety models in experimental animals

Hüseyin Günay

Etimesgut Military Hospital, Psychiatry Clinic, Ankara, Turkey E-mail: [email protected]

The basic measure in testing validity of an animal model is its prediction validity, which means making true assumptions for a disorder in humans. The necessary features of an animal model are analogy to a disorder in humans, objective testing, effective interventions in humans and the capability of retesting. Structural validity is the capability to retest of the target condition and first sight validity is the measurement of phenomenological similarity. First sight validity points to the surface similarity between the model and the disease and structural validity points to the underlying mechanisms. Anxiety models are mainly used in understanding causes and mechanisms and also determining drug effects. Anxiety in animals, which is similar to humans, can be developed with different environmental conditions. These situations can help to understand and intervene to treat anxiety. Three ways are used in the development of anxiety models: using a new environment, reward and punishment applications, and punishment procedures. Anxiety models using new environment: These are the methods for establishing and evaluating anxiety models in a new environment, such as elevated plus maze and derivers, elevated T-maze, open field, staircase test, social isolation, novelty suppressed feeding, social interaction, holeboard, predatory odor, operant conflict tests for reward-punishment applications and experiments with punishment procedures such as defensive burying, passive avoidance, foot shock, hot plate and four plate tests.

S68 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

The purpose of this study is to show the usefulness of the tests in the literature and to compare the advantages and disadvantages in terms of structural validity and first sight validity. Key words: Anxiety, anxiety models

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S68-9

[PS-10] Symposium Title: Will glutamatergic modulators be a target for the future therapy of depression? Ketamine and other glutamate modulators as potential antidepressants

Serdar Dursun, Glen Baker, Nick Mitchell

Neurochemical Research Unit, University of Alberta, Edmonton, Canada E-mail: [email protected]

Depression is seen as a complex neuropsychiatric disorder affecting integrated pathways connecting discrete cortical, subcortical, and limbic regions and their associated neurotransmitter and molecular mediators. One episode of major depression is a strong predictor of future episodes, and more than 50% of individuals who have an episode of major depression experience a recurrence. Unfortunately, currently approved pharmacological treatments for depression require several weeks for onset of efficacy. Despite advances in the understanding of the psychopharmacology of depression and the introduction of several novel classes of antidepressants in the last 3-4 decades, patient response to any given pharmacological approach continues to be unsatisfactory. Although almost all of the prescription drugs currently available as antidepressants have effects on noradrenaline (NA) and/or 5-hydroxytryptamine (5-HT), it is obvious that other factors are also important in the etiology and pharmacotherapy of depression and that the monoamines cannot be considered in isolation. Perhaps the most exciting system and that for which there is now substantial translational evidence for a role in depression is that involving glutamate. Ample evidence indicates that glutamate homeostasis and neurotransmission are disrupted in major depressive disorder but the nature of these disruptions and the mechanisms by which they contribute to the syndrome are unclear. Likewise, the specific effects of existing antidepressants on glutamate are unclear, as is the potential of drugs directly targeting glutamatergic neurotransmission to act as novel antidepressant medications. However, these are areas of active research and some exciting results have been obtained. This presentation will review the current knowledge of the contribution of the N-methyl-D-aspartate (NMDA) receptor, one of the several types of glutamate receptors, to depression and its treatment. Several lines of evidence, in humans and in animal models, support the contention that neurotransmission via the NMDA receptor is dysregulated in depression. Drugs targeting the NMDA receptor as antagonists have shown antidepressant properties in both clinical and preclinical studies. Nevertheless, other effects of such medications, including both cognitive side effects and their psychotomimetic properties, complicate such an application and represent a challenge to the development of clinically useful agents. There is a recent hypothesis that the therapeutic effects of monoaminergic antidepressants and the NMDA receptor antagonist ketamine may be mediated by increased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-to-NMDA glutamate receptor activity in critical neuronal circuits. It has been hypothesized that ketamine directly mediates this receptor activity, whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of clinical improvement of several weeks that is observed with traditional antidepressants. Ketamine (intravenous) is the first medication reported to produce rapid, relatively long- lasting antidepressant efficacy. Although the precise antidepressant mechanisms of action of ketamine remain unclear, there is preclinical evidence to suggest that both AMPA and NMDA receptor subtypes are involved. In terms of neuroanatomical sites of action, it has been shown that the subgenual cingulate cortex (Sg CG) is overactive in depression while the dorsal frontal regions and posterior cingulate are underactive and that successful treatment normalizes the pattern. There is also evidence from functional magnetic resonance imaging (fMRI), which has demonstrated that the effect of ketamine resembles the pattern of normalisation after successful antidepressant treatment, i.e., in healthy volunteers there is decreased orbitofrontal cortex (OFC)–Sg CG blood oxygen level-dependent (BOLD) signal response and increased BOLD signal response in the dorsolateral prefrontal cortex (PFC) (Brodmann area 8) and the posterior cingulate region. These findings suggest that an overactive Sg CG may be the dysfunctional organising region in depression. Key words: Ketamine, rapid antidepressant efficacy, glutamate, NMDA receptor

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S69

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S69 Abstracts of the Invited Speakers

The glutamatergic system and its importance in the neurobiology of depression

Feyza Arıcıoğlu

Department of Pharmacology, Marmara University, Istanbul, Turkey E-mail: [email protected]

Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder affecting millions of individuals worldwide. Current medications for the treatment of depression have limited efficacy and delayed onset of therapeutic action. Existing antidepressants used to treat these disorders are insufficient for many. Patients continue to have low remission rates, delayed onset of action, residual subsyndromal symptoms, and relapses. New therapeutic agents able to exert faster and more sustained antidepressant effects are urgently needed to treat these disorders. Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Patients with depression have been found to exhibit increased blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to be involved in depression. Activation of inflammatory pathways is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with findings that characterize depressive disorders. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are involved in the pathogenesis of mood disorders and in the action of at least some drugs. It has been shown that serum BDNF levels are decreased in patients with depressive disorder and antidepressant treatment induces BDNF expression. In this context, the glutamatergic system has been implicated in the pathophysiology of depression in unique clinical and neurobiological ways. The data from depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. The past decade of efforts to find improved treatment for depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. To date, the monoaminergic systems (serotonin, norepinephrine, and dopamine) have received the most attention in the neurobiology of depression, and all classes of antidepressants target these monoaminergic systems. Accumulating evidence suggests that the glutamatergic system plays an important role in the neurobiology and treatment of depression. Many reports have highlighted alterations in glutamate signaling as well as changes in the expression of AMPA or NMDA receptor subunits in depression. In parallel, there is growing interest in the non-competitive NMDA receptor antagonist, ketamine, which produces a rapid and sustained antidepressant response in patients with treatment-resistant depression. Importantly, such effects of ketamine are seen at subpsychomimetic doses of the drug. Moreover, ketamine produces a profound reduction in suicidality. Based on findings with ketamine, there is interest in developing subtype-selective NMDA antagonists, particularly those that act through allosteric mechanisms. A final glutamatergic strategy for treating depression may be through modulating metabotropic (G protein-coupled) glutamate (mGlu) receptors. During the last 10 years, several selective mGlu receptor competitive antagonists and potentiators have been discovered. Selective mGlu receptor antagonists are among the most promising agents under development for the treatment of depression. Overall, this system holds considerable promise for developing the next generation of therapeutics for the treatment of depression. Key words: Glutamate, depression, cytokines, neurotrophic factors, NMDA, mGLU receptors

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S70

[PS-11] Symposium Title: Psychotropic drug treatments during pregnancy and lactation Pharmacotherapy of panic disorder during pregnancy and lactation

Faruk Uğuz

Selcuk University, Meram Faculty of Medicine, Department of Psychiatry E-mail: [email protected];[email protected]

Panic disorder is one of important psychiatric problems during pregnancy and lactation. The prevalence rate of this disorder has been reported to be 0.4%-4.0% in the perinatal period. In addition, the perinatal period may affect the onset or course of panic disorder. Although pharmacotherapy of panic disorder is well known, data on treatment of this disorder during pregnancy and lactation are very limited. It is difficult to decide about pharmacotherapy of panic disorder during the perinatal period, particularly during pregnancy,

S70 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers because both effective pharmacological agents and untreated maternal anxiety seem to be associated with several negative outcomes on the course of pregnancy and the fetus. Despite the absence of practical guidelines for pharmacological management of panic disorder during pregnancy and lactation, some general points about pharmacological treatment include the following: (1) Pharmacotherapy should be preferred when the potential impact of untreated maternal panic disorder is higher than the impact of the pharmacological agent on the fetus or new mother. (2) The patient and relatives should be informed about the benefits and risks of pharmacological treatment or nontreatment of the current maternal psychiatric picture and written informed consent forms should be obtained. (3) Selective serotonin reuptake inhibitors except paroxetine and low dose imipramine may be preferred during pregnancy. (4) Sertraline, paroxetine, orlow doses of imipramine or clomipramine appear to be appropriate pharmacological agents during the lactation period. Key words: Panic disorder, pregnancy, lactation

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S70-1

Psychotropic drug treatment during pregnancy and lactation in obsessive compulsive disorder

Servet Ebrinç

GATA Haydarpasa Training Hospital, Clinic of Psychiatry, Istanbul, Turkey E-mail: [email protected]

According to recent studies, obsessive compulsive disorder(OCD) is one of the leading cause of disability and the prevalence of OCD is found to be 0.2-3.5% in pregnancy and 2.7-9% in the postpartum period. The efficacy and tolerability of SSRIs and SNRIs in the treatment of OCD are well-determined in many double-blind randomized controlled trials. Despite the fact that it is well known that OCD patients may benefit from antiobsessional therapy during pregnancy and the postpartum period, very little data are available about the efficacy of the treatment and no evidence suggests that patients would react differently to these drugs. Hence, OCD women who are pregnant and in the postpartum period might be treated using standardized treatment approaches. During pregnancy and the postpartum period, the treatment of OCD should clinically take the risks and benefits of several treatment modalities and the expectations of the patient into account. While cognitive-behavioral therapy (CBT) is the leading choice in non- pharmacological treatment of OCD, pharmacoterapy might be used if necessary. If CBT is inadequate and pharmacotherapy is needed, during pregnancy, fluoxetine, and during the lactation period, paroxetine, are proposed to be the first line treatments. Although evidence is limited, other SSRIs are acceptable as alternative treatment options. All of the antidepressant drugs are transferred to the nursing infant during breastfeeding. The American Academy of Pediatrics classifies psychotropic drugs as “drugs whose effects are unknown, but may be of concern.” The best way of determining the exposure to the drug is measuring the drug concentration in the plasma of the baby. Clinical evaluation is important to identify any side effects while monitoring the baby. There is no evidence indicating an increase in the rates of intrauterine death or malformation in the case of exposure to tricyclics or SSRIs. Whether exposure to SSRIs causes a decrease in birth weight or an increase in premature births is not certain and the evidence is controversial. Nonetheless, The Food and Drug Administration (FDA) has determined that first trimester exposure to paroxetine might cause an increase in the risk for congenital malformations particularly cardiac defects. Therefore, the FDA has changed paroxetine’s pregnancy category from C (risk can not be ruled out) to D (positive evidence of human fetal risk). A “withdrawal syndrome,” consisting of symptoms in the locomotor, central nervous, respiratory and gastrointestinal systems may occur in newborns exposed to SSRIs in the third trimester. Although monitoring is required in an exposed newborn, this syndrome is relatively mild, can be managed with supportive therapy and diminishes within 2 weeks. Some evidence points out an increase in the rates of persistent pulmonary hypertension in infants exposed to SSRIs during the third trimester. Before delivery, lowering the dosage of the mother’s drugs that might have been augmented due to the symptom severity of OCD, is recommended. Key words: lactation, obsessive-compulsive disorder (OCD), psychopharmacotherapy, pregnancy

References: 1. Clinical Management Guidelines for Obstetrician-Gynecologists Use of Psychiatric Medications During Pregnancy and Lactation. ACOG Practice Bulletin, (Reprinted with permission from Obstetrics & Gynecology 2008; 111:1001–1020) 2. Brandes M, Soares CN, Cohen LS. Postpartum onset obsessive-compulsive disorder: diagnosis and management. Arch Womens Ment Health 2004; 7:99–110 3. Use of Psychoactive Medication During Pregnancy and Possible Effects on the Fetus and Newborn Amerikan Academy of Pediatrics Committee on Drugs Pediatrics 2000; 105; 880-887 4. Koran LM, Hanna GL, Hollander E et al. Practice Guidline for theTreatment of Patients with Obsessive-Compulsive Disorder. Copyright 2010, American Psychiatric

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Association. 5. McGuinness M. OCD in the Perinatal Period: Is Postpartum OCD (ppOCD) a Distinct Subtype? A Review of the Literature. Behavioural and Cognitive Psychotherapy 2011, 39, 285–310

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S71-2

[PS-12] Symposium Title: Vitamin and mineral supplementation in treatment of childhood psychiatric disorders Vitamin and mineral supplementation in treatment of childhood psychiatric disorders – Calcium and vitamin D supplementation

Ömer Faruk Akça

Samsun Psychiatry Hospital, Child and Adolescent Psychiatry Clinic, Samsun, Turkey E-mail: [email protected]

Vitamin D has significant roles in cell proliferation, the immune system and the nervous system as well as in bone development. Adult studies indicate that vitamin D deficiency may be related to some neurological and psychiatric disorders like Parkinson’s disease, Alzheimer’s disease and depression (1). Childhood studies on this subject are mainly related to the impact of vitamin D deficiency on the development of autism. Because vitamin D has an essential role in the development of the nervous system, some investigators suggest that vitamin D deficiency during pregnancy may contribute to the development of autism. Autism is stated to be more frequent in people with dark skin and people who live in countries at higher latitudes. Additionally, children of mothers who consume more vitamin D in pregnancy have better mental development and present with fewer autistic signs. This knowledge indicates that vitamin D may be a mediator in the emergence of autism for genetically vulnerable people (2). Autism frequency has increased in recent years and this increase has occurred at the same time as the suggestions on the avoidance of sunlight have arisen. This coincidence is claimed to be supportive of the autism-vitamin D hypothesis (2,3). This hypothesis suggests two possible mechanisms: 1) vitamin D deficiency during pregnancy may cause inappropriate development of the fetal brain and then autistic signs may emerge, 2) in light of the hypotheses that autism is an autoimmune disorder and vitamin D is important for immune system functions, it may be assumed that vitamin D deficiency may cause autistic signs in vulnerable individuals (4). Some studies have stated that autism is more frequent in children of winter pregnancies and people of higher latitude countries (4). Additionally, it is stated that autistic patients have the lowest vitamin D levels among all kinds of psychiatric disorders in a psychiatry inpatient clinic (5). In another recent study, autistic children have lower 25-hydroxy vitamin D, 1,25-hydroxy vitamin D and calcium levels in comparison with healthy children (6). These findings are supportive of this hypothesis. According to this hypothesis, it can be estimated that children with rickets would have more autistic symptoms. There is no recent study on this assumption. However, in past studies it has been stated that these children had more mental disorders, which disappeared after treatment (7). On the other hand, because children with autism may have food selectivity, vitamin D and calcium deficiency may occur in these children more frequently. Some investigations were made on this subject and many of them found supportive findings (8,9). We may conclude that autism-vitamin D relationship needs to be investigated more with larger sample studies. Key words: Autism, vitamin D, calcium

References: 1. Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol 2011; Article in press. 2. Cannell JJ. Autism and Vitamin D. Med Hypotheses 2008; 70: 750-759 3. Cannell JJ, Hollis BW. Use of Vitamin D in Clinical Practice. Altern Med Rev 2008; 13:6-20. 4. Grant WB, Connie MS. Epidemiologic evidence supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism. Dermatoendocrinol 2009; 1:223-228. 5. Humble MB, Gustafsson S, Bejerot S. Low serum levels of 25-hydroxyvitamin D (25-OHD) among psychiatric out-patients in Sweden: relations with season, age, ethnic origin and psychiatric diagnosis. J Steroid Biochem Mol Biol 2010;121:467-470. 6. Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced Serum Levels of 25-Hydroxy and 1,25-Dihydroxy Vitamin D in Egyptian Children with Autis J Altern Complement Med 2010; 16:641-645. 7. Cannell JJ. On the aetiology of autism. Acta Paediatr 2010; 99:1128–1130. 8. Zimmer MH, Hart LC, Manning-Courtney P, Murray DS, Bing NM, Summer S. Food Variety as a Predictor of Nutritional Status Among Children with Autism. J Autism

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Dev Disord. 2011 Article in press. 9. Emond A, Emmett P, Steer C, Golding J. Feeding Symptoms, Dietary Patterns, and Growth in Young Children With Autism Spectrum Disorders Pediatrics 2010; 126:337-342.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S72-3

Zinc supplementation in psychiatric disorders of children

Sadriye Ebru Çengel Kültür

Department of Child and Adolescent Psychiatry, Hacettepe University, Ankara, Turkey E-mail: [email protected];[email protected]

Micronutrient supplementation is considered as a useful intervention in many cases. Zinc is one of these micronutrients and an essential cofactor for over 100 enzymes, both metalloenzymes and metal-enzyme complexes that are required in the metabolism of carbohydrates, fatty acids, proteins and nucleic acids. Zinc is considered as an essential element in neuronal development, synaptogenesis and synaptic transmission. In experimental animal studies, zinc deficiency during early brain development is mainly related with malformations. In humans, neuropsychological and neurobehavioral effects of zinc deficiency are largely studied in severely zinc deficient groups or cases exposed to deficiency during early developmental stages. In addition zinc supplementation studies mainly occur in the gestational period or infancy and use zinc doses higher than the protective dosage. Limited numbers of interventional trials have been performed to demonstrate the effects of zinc supplementation on behavioral, cognitive and neuropsychological functioning in school-aged children. Some of these studies showed no significant effects on average attention span and short-term memory. On the other hand some found improvement in neuropsychological performance and decrease in the number of children with clinically significant parents’ scores for attention deficit and hyperactivity. When searched for internalizing symptoms, no significant effect was revealed in parent-teacher rated scales. In clinical cases with attention deficit hyperactivity disorder (ADHD) and autism low serum zinc levels were reported. Zinc supplementation studies in ADHD cases showed significant improvement reported in parents’ and teachers’ ratings of hyperactivity, impulsivity and socialization scores. Furthermore, one study found that improvement was mainly in parent-teacher-rated inattentive symptoms in ADHD cases. In a placebo controlled study, zinc supplementation in addition to ADHD treatment revealed a 37% reduction in d-amphetamine dose compared to placebo, though no significant superiority of zinc supplementation for ADHD symptoms was observed. In conclusion, zinc supplementation studies suggest a special relationship to ADHD diagnosis. However it is not possible to establish either an etiological relation or an alternative treatment approach in ADHD. Key words: Zinc supplementation, ADHD

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S73

The impacts of iron deficiency on mental health in childhood

Ayhan Bilgiç

Department of Child and Adolescent Psychiatry, Meram Faculty of Medicine, Selcuk University, Konya, Turkey E-mail: [email protected]

Numerous studies have found associations between iron deficiency (ID) and iron deficiency anemia (IDA) and poor cognitive and motor development in infancy and early childhood. In addition, it has been reported that there are associations between ID/IDA and some childhood neuropsychiatric disorders including attention deficit hyperactivity disorder, conduct disorders, autism spectrum disorders, restless leg syndrome, sleep disturbance and Tourette’s syndrome. Iron is required for proper function of some enzymes that are engaged in the myelinization process and in monoamine neurotransmitter synthesis. Therefore, it has been considered that these negative effects of ID and IDA are related to the vital roles of iron in the brain. Thus, authors have suggested that the presence of ID without anemia is sufficient for occurrence of functional disturbances, although exceptions exist. There are studies which considered that, especially early in life, the negative impacts of ID on psychomotor and neurological development do not seem to be reversible by iron supplementation and ID may cause permanent hazards in the brain. However, some studies have reported that iron supplementation resolved the effects of ID including cognitive and motor development problems in children and the development of psychiatric disorders. Despite there being

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S73 Abstracts of the Invited Speakers large amounts of data, the possible confounding effects of poor socioeconomic backgrounds prevent causal inferences. Even nowadays, it is still not clear whether poor development of iron-deficient children is related to poor social backgrounds or irreversible damage due to ID and if it is remediable with iron treatment. Key words: Iron deficiency, children, development, psychiatric disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S73-4

Antioxidant vitamin supplementation therapies in child psychiatry

Betül Mazlum

İstanbul University, Institute of Experimental Medicine, Department of Neuroscience, İstanbul, Turkey E-mail: [email protected]

Oxidative stress can be defined as an imbalance between pro-oxidant molecules produced by the body during metabolism and members of the antioxidant system, in favor of the former. Antioxidant defense mechanisms include antioxidant enzyme systems and molecules (vitamins, minerals, etc.) which have the ability to detoxify free oxygen radicals. The brain is highly vulnerable to oxidative stress since it has limited antioxidant capacity, high energy demand and high lipid content. Moreover, each brain region may have a genetically determined different vulnerability levels to oxidative stress. Oxidative stress, which is included in the pathogenesis of cancer, aging, cardiovascular and neurodegenerative disorders, is also considered for pathogenetic mechanisms underlying psychiatric disorders including schizophrenia, bipolar disorder, depression, autism and attention deficit hyperactivity disorder. There are accumulating data about increased oxidative stress particularly in childhood autism and therefore antioxidant therapies are considered as an alternative treatment option. In addition, vitamin and mineral supplementation are recommended to compensate low intake when children with autism have feeding problems. The data about the effects of antioxidant therapies in autism are restricted but promising. Since oxidative stress is a common finding in the pathogenesis of different disorders, it can be suggested that individual differences, including single nucleotide polymorphisms of the genes coding for members of the antioxidant defense system, might determine the vulnerability level to oxidative stress. Individual genetic differences might also be the determinant of the level of benefit from antioxidant vitamin therapies. Not only the factors related to the biochemistry of leading antioxidant vitamins (vitamin A, C and E) but also the disease and patient related differences might be acting on the response to supplementation with these vitamins. These two groups of factors might determine the details of supplementation therapies with antioxidant vitamins in the future: 1) Factors related to the patient and the nature of the disease, i.e. the affected brain areas for a specific disorder, the vulnerability of these brain areas to oxidative stress, accompanying diseases and possible effects of antioxidant vitamin supplementation on the pathogenesis of these comorbid diseases; 2) Factors related to the biochemistry of the antioxidant vitamins in the body, i.e., polymorphisms of molecules mediating intestinal absorption and blood-brain transfer of vitamins, important effects of these vitamins on specific gene regulation and effects of vitamins on brain mechanisms. Antioxidant vitamin supplementation is a promising alternative therapy in psychiatry, but it should be kept in mind that these vitamins might also have undesirable results through their effects on other biological processes. This part of the panel will focus on the study results of antioxidant vitamin supplementation therapies in child psychiatry and molecular data about the genetic and biochemical processes of antioxidant vitamins in the body. Key words: Antioxidant vitamins, psychiatry

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Effectiveness of omega fatty acid supplementation for childhood psychiatric disorders

Sabri Hergüner

Selcuk University, Meram Faculty of Medicine, Department of Child and Adolescent Psychiatry, Konya, Turkey E-mail: [email protected]

Neuronal membranes are composed of phospholipids containing large amounts of polyunsaturated fatty acids (PUFA), especially the omega-3 and omega-6 acids. Because humans cannot manufacture these de novo, they are “essential” in the diet. Membrane stability is

S74 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers essential for neuronal maturation as well as for advanced integrated central system activities including attention, alertness and motor coordination. PUFA are critically important for normal brain development and functioning. During fetal life, large amounts of PUFA are deposited in the central nervous system. During infancy, dietary intake of PUFA, both omega-3 and omega-6 acids, continues to be essential for neural development. PUFA are metabolized to prostaglandins and other eicosanoids, which modify many metabolic processes and immune functions. They moderate dopamine, serotonin and norepinephrine release, regulate gene transcription and Na-K-ATPase channel function. There is increasing evidence that omega acids play a part in many neurodevelopmental and psychiatric disorders including attention deficit hyperactivity, dyslexia, developmental coordination disorder and autism spectrum disorders. The focus of this speech will be on the effects of PUFA supplementation on pediatric neurodevelopmental disorders. Key words: Children, neurodevelopmental disorders, omega fatty acids

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S74-5

[PS-13] Symposium Title: Hormones and psychiatric disorders Melatonin and human behaviour

Müfit Uğur

İstanbul Üniversitesi, Cerrahpaşa Tıp Fakültesi, Psikiyatri AD, Cerrahpaşa, İstanbul, Turkey E-mail: [email protected]

Melatonin is secreted from the pineal gland and regulates the sleep wake cycle, core body temperature, ovulation, and sexual behavior in females, as well as immune and cardiovascular functions. It also has antioxidant, antiinflammatory, and glucose regulatory properties. Melatonin also changes behavior especially in depressed patients or patients who are prone to a psychiatric illness. External noradrenergic stimuli act on the suprachiasmatıc nuclei and control melatonin secretion, which in turn regulates autonomic functions and daily behaviors by acting as an endogenous synchronizer. Melatonin, which manages body core temperature, the sleep wake cycle, and gonadal sex steroids, also causes some behavioral problems in case of depression. In bipolar manic patients nocturnal melatonin is found to be higher than in depressed patients because of noradrenergic stimulation. Melatonin secretion and body core temperature are also closely related. Core body temperature is the lowest when the nocturnal melatonin secretion is high. By controlling core body temperature, melatonin also helps to regulate the body metabolism and glucose utilization. Ovulation in females is under the control of melatonin. When melatonin is the lowest nocturnally, which causes high core body temperature, it is time for ovulation in females. High core body temperature and low nocturnal melatonin secretion return to normal after the ovulation occurs. It also controls the secretion of sex steroids by its suppressive effect on the gonads. Nowadays some research is working on using it as an oral contraceptive agent. It also regulates immune functions by acting on T lymphocytes and help organisms to have a high defense against infections, supplying an anti-inflammatory effect and serving as an antitumor agent. Today it is used specifically for the treatment of sleep disorders such as: -Advanced sleep phase syndrome -Delayed sleep phase syndrome -Circadian rhythm disorders -Insomnia -Irregular sleep wake cycle -Jet-Lag -Seasonal affective disorders -REM related behavior disorders Key words: Melatonin

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S75

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S75 Abstracts of the Invited Speakers

Effects of oxytocin on social behaviour

Nuray Atasoy

Zonguldak Karaelmas University, Faculty of Medicine, Psychiatry Department, Zonguldak, Turkey E-mail: [email protected]

Oxytocin (OXT) is traditionally viewed as a female hormone that is primarily associated with labor and it has a very special affect on mothering. In mothers it increases their attachment to their infant, promoting the feeling of love, and makes her infant more valuable to her. Oxytocin has been called the love and bonding hormone. Furthermore, oxytocin mediates attachment behavior over the course of development, with lower urinary concentrations of oxytocin found in maltreated children and in adult males with a history of early separation. Psychologically, oxytocin promotes a feeling of well being and tranquility. It also suppresses the fear that would normally cause a mother to back off from a threat. In humans, based on the animal literature, it has been postulated that beyond these peripheral actions, central OXT modulates cognition in the context of social interactions, thus promoting positive sociality. In particular, recent experiments have shown that OXT promotes trusting behavior, enhances facial emotion recognition and memory for positive social information, reduces social stress, improves social cognition in socially impaired individuals with autism, and alters dysfunctional cognition in social phobia. Functional imaging studies have just begun to elucidate the underlying neural correlates of these pro-social effects. A number of studies have provided evidence that the amygdala might be a key structure for the mediation of the social cognitive effects of OXT. Several studies have shown that a single dose of OXT reduced amygdala reactivity to pictures of aversive scenes and faces with negative valence. While studies of oxytocin and monogamous behavior in humans have not been conducted to date, one study found that in co-habiting couples, greater partner support is associated with higher plasma oxytocin in both men and women before and after a period of warm partner contact. The OXT system is a sexual dimorphic system. For example, OXT plasma levels tend to be higher in females and synthesis, as well as OXT receptor affinity, appears to be modulated by gonadal steroids such as estradiol and progesterone. It has been shown, in a study on prairie voles, that female parenting behavior is more dependent on OXT, whereas male parenting behavior is associated with vasopressin. Another study demonstrated that aggression is associated with OXT in females, but not in males. However, the hypothesis of homology between paternal and maternal behavior has not yet been adequately tested and it is possible that different neuroendocrine circuits could lead to the same behavior in males and females. Future studies should include both sexes to determine a possible sexual dimorphism in the neural effects of OXT, considering gonadal steroids and OXT receptor affinity. Key words: Oxytocin, social behaviour

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Thyroid hormones and psychiatric disorders

Tayfun Turan

Department of Psychiatry, Erciyes University, Kayseri, Turkey E-mail: [email protected]

The role of the hypothalamic-pituitary-thyroid (HPT) axis in psychiatric symptoms and disorders has been stressed in many studies. Secretion of thyroid hormones is controlled by this axis. Hypothalamic thyrotropin releasing hormone (TRH) stimulates pituitary thytrotropin-stimulating hormone (TSH) and the latter controls the secretion of thyroid hormones. Serum thyroid hormones regulate the HPT axis by a negative feedback system. The main secretion of the thyroid gland is thyroxine (T4). T4 is converted into triiodothyronine (T3) in various tissues, especially in brain, by enzymes called “deiodinases”. Transthyretin, a hormone transporter, transports T4 into the brain (1). Thyroid hormones play a critical role in the developing and functioning of the brain (2). In this regard, it is suggested that interactions between thyroid hormones and neurotransmitter systems, especially serotonin (5-HT), norepinephrine (NE) and acetyl choline (Ach), probably contribute to the regulation of mood and behaviour (1). T3 enhances the effects of NE, 5-HT and γ-aminobutyric acid, which are thought to be involved in the etiology of some psychiatric conditions (3). In the literature there are many case reports and studies indicating probable relationships between clinical or subclinical thyroid diseases and psychiatric disorders. So far, many cases have been reported of hypothyrodism or hyperthyroidism associated with psychiatric disorders, including mania, depression, schizophreniform psychosis, paranoid psychosis, cognitive disturbances, delirium and anxiety

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(4-9). One percent of thyrotoxic patients are suggested to have been first diagnosed with a psychiatric disease (5). Interestingly, it seems that both hyperthyroism and hypothyroidism could lead to mania, anxiety or schizophrenic symptoms. The underlying reason for the co-occurrence of thyroid diseases and psychiatric disorders is not yet known. However, in these cases, combined hormonal and psychotropic interventions may improve symptoms. Several studies have assessed HPT axis activity in various psychiatric disorders, especially mood disorders and anxiety disorders. Up to 45% of the euthyroid patients with major depression showed blunted TSH response to TRH stimulation (10). Moreover, thyroid hormones accelerate the antidepressant effect of tricyclic antidepressants (11). HPT axis alterations may play an important role in the pathophysiology of bipolar disorder, but this area has received much less attention than major depressive disorder. However, it seems that abnormalities of this axis are not uncommon among bipolar patients, especially among the rapid cycling subgroup. So far, thyroid dysfunctions such as hypothyroidism and exaggerated TSH response to TRH have been found in rapid cycling patients (12,13). In some bipolar patients, latent thyroid dysfunction becomes overt by lithium treatment. Moreover, it has been suggested in a recent study that bipolar disorder itself may cause increased thyroid volumes and decreased thyroid hormones as well as lithium treatment in patients (14). Few studies have investigated possible thyroid dysfunctions in psychotic patients. In a study, schizophrenic patients showed increased serum T4 levels, which normalized after antipsychotic treatment. Elevated serum T4 levels in schizophrenic patients may suggest an impairment of T4 metabolism in the brain (4). A few studies of panic disorder have demonstrated evidence of a blunted TSH response to TRH. A previous study showed higher TSH levels in non-medicated patients with severe panic attacks (7). Increased TSH levels seen in patients with panic disorder might be due to reduced intracerebral 5-HT concentrations (15). Eletroconvulsive therapy (ECT) itself may affect the HPT axis as do psychotropic drugs. In a previous study, elevated TSH levels were found following ECT in depressed patients. This response might contribute to the therapeutic effect of ECT (16). In conclusion, the HPT axis and thyroid hormones play an important role in the pathophysiology of many psychiatric disorders. However, further well-designed studies are needed to clarify the confusion in this field. Key words: Hypothalamic-pituitary-thyroid axis, thyroid hormones, psychiatric disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S76-7

Sex steroids and psychiatric disorders

Erdem Deveci

Regional Training and Research Hospital, Department of Psychiatry, Erzurum, Turkey E-mail: [email protected]

Sex steroids play very important roles in the development and function of the central nervous system and have long been known to exert powerful effects on brain differentiation, neural plasticity, central neurotransmission and behavior. Estrogens, progestins, and androgens are able to induce several effects in brain areas of the central nervous system, through binding with specific receptors (1). Sex steroid hormones act through genomic mechanisms, modulating synthesis, release and metabolism of many neuropeptides and neurotransmitters, and through non-genomic mechanisms, influencing electrical excitability, synaptic function, morphological features and neuron-glia interactions (2). Animal research has shown that estrogens, progesterone and testosterone are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. Animal studies have also provided evidence that estrogen modulates dopaminergic activity and affects dopamine related behaviors in animals in a variety of ways. Clinical observations suggest that sex steroids have potent effects on mood, mental state and cognitive functions. Data also suggest that estrogen has a pivotal role in modulating other neurotransmitter systems such as serotonergic and glutamatergic systems that have implications for schizophrenia and mood disorders (3,4). Sex steroid deficiency causes many neuroendocrine changes. At the hypothalamic level, estrogen withdrawal gives rise to vasomotor symptoms, eating behavior disorders, and altered blood pressure control. On the other hand, at the limbic level, the changes in serotoninergic, noradrenergic and tones contribute to modifications in mood, behavior and nociception. Studies of testosterone concentrations in depression have yielded inconsistent results reporting low as well as high testosterone levels associated with depression (5). On the other hand anabolic steroid use has increased in prevalence in many countries over the past decade, and it can lead to aggression, depression, mania and psychosis, in addition to a range of physical complications which seem to be important in clinical practice (6). Key words: Depression, estrogen, mood disorders, progesterone, schizophrenia, testosterone

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References: 1. McEwen BS Steroid hormones are multifunctional messengers to the brain. Horm Res. 1992; 37(Suppl 3):1-10. 2. Genazzani A.R. et al. Endocrinology of Menopausal Transition and Its Brain Implications CNS Spectr. 2005 Jun;10(6):449-57. 3. Janice R, Stevens MD Schizophrenia: reproductive hormones and the brain. Am J Psychiatry 2002; 159:713-719. 4. Seeman MV. The role of estrogen in schizophrenia. J Psychiatry Neurosci 1996; 21:123-125. 5. Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract 2009;15:289-305. 6. Hall, R. C. W., Hall, R. C. W. & Chapman, M. J. Psychiatric complications of anabolic steroid use. Psychosomatics, 2005; 46- 285.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S77-8

Insulin and psychiatric disorders

Mesut Cetin

Department of Psychiatry, GATA Haydarpasa Training Hospital, Uskudar, Istanbul, Turkey E-mail: [email protected]

Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin also influences other body functions, such as enhancing acute thermoregulatory and glucoregulatory responses to food intake. It is also a neuropeptide transmitter and enhances learning and memory. Hypoglycemia is a lack of sufficient glucose and a scarcity of the sources of glucose, which can dramatically manifest itself with impaired functioning of the central nervous system and can cause dizziness, speech problems, and even loss of consciousness. While producing those symptoms, hypoglycemia also provokes a rapid increase in epinephrine secretion, which leads to tremulousness, lightheadedness, perspiration, anxiety, hunger, nausea, and tachycardia. These symptoms present like a panic attack, suggesting that if hypoglycemia does provoke anxiety attacks it may be through its action as a nonspecific stressor, perhaps by interacting with an underlying CNS disorder that predisposes to panic. The fear of hypoglycemia-induced bodily symptoms of arousal has been implicated in the pathogenesis of both spontaneously occurring and experimentally provoked panic attacks. The fear of bodily symptoms may be a characteristic of panic disorder and is hypothesized to predict state anxiety and panic frequency during experimentally induced peripheral arousal. Insulin resistance and metabolic syndrome (MS) have become worldwide problems. MS is a cluster of risk factors associated with increased risk of cardiovascular diseases and type 2 diabetes. Based on research data from 2004, 40% of adults in Turkey meet the criteria for diagnosis of metabolic syndrome. The use of certain medications, such as atypical antipsychotics, may increase insulin resistance and the risk of the metabolic syndrome. Key words: Insulin, panic disorder, insulin resistance, hypoglycemia, depression

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S78

[PS-14] Symposium Title: Clinical course of psychiatric disorders associated with trauma and treatment issues Trauma and mood disorders

Medine Yazıcı Güleç

Erenkoy Mental Research and Training Hospital, Istanbul, Turkey E-mail: [email protected], [email protected]

There is increasing evidence for the role of adverse childhood experiences in the occurence of mood disorders (MD). A great number of studies have shown that there is a correlation between MD and parental indifference, neglect and sexual and physical abuse. Angst et al., in a 20-year longitudinal study, suggested that childhood family issues have a robust correlation with the chronicity of bipolar and unipolar MD, and adverse childhood experiences give rise to low self-esteem and anxious personality. The presence of childhood trauma (CT) has found to be associated with increases in rates of substance abuse, early age of onset, rapid cycling, and suicide. There is severe CT in half (49%) of bipolar MD patients.

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Individuals with CT have both an overall increased risk for depression and a substantially increased sensitivity to the depressogenic effects of stressful life events. The relation between CT and stressful life events is dose dependent and correlated with the intensity of the neuroticism. It has been shown that the severity of CT predicts an early age of onset and the number of life time depressive episodes, and that it is associated with more comorbidity. Increased rates of emotional CT, depressive symptoms and anxiety have been reported in treatment resistant group of patients. Childhood adverse life events are associated with various neuroendocrine and neuroanotomical changes. There is a 6 times larger ACTH response to stress in depressive female patients who reported CT. These patients also have an increased cortisol response and heart rate response to psychosocial stress. Women, who have reported CT but were not depressed, have exhibited normal cortisol responses, despite having increased an ACTH response. This can be interpreted as resilience against depression, an adrenal adaptation to central sensitization. It has been reported that decreased hippocampal volume (18%) in depression is related to CT and that the hippocampal volumes of depresssive patiens who did not report CT were equal to those of the control group. Repeated bursts of CRF in response to stress during development and increased cortisol reactivity over the course of time may contribute to smaller hippocampi after childhood trauma exposure, leading to further sensitization of the stress responses. These results would suggest that there are biologically distinct subtypes of depression as a function of childhood trauma. The effect of CT on predisposition to illness is associated with genotype. The s/s allele of the serotonin transporter gene, the gene polymorphism of BDNF and the CRF-1 gene have been shown to be related to vulnerability to trauma effects. CT is associated to decreased response to pharmacological treatment. Among chronically depressed patients with no history of early trauma, combination treatment was most effective in attaining remission compared to pharmacotherapy and psychotherapy. In contrast, in chronically depressed patients with early-life trauma, remission rates were significantly higher for psychotherapy alone versus pharmacotherapy. Combination treatment did not have any further advantage over psychotherapy alone. Improved effects of cognitive and behavioral therapies, group therapies and EMDR have been reported in various studies. Questioning about CT in MD patients seems to be important for treatment planning, assessment of risks and prophylactic interventions. Key words: Childhood trauma, mood disorders

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S78-9

Trauma and psychotic disorders

Selma Bozkurt Zincir

Erenkoy Mental Health and Diseases Training and Research Hospital, Istanbul, Turkey E-mail: [email protected]

In recent years, there has been a growing awareness of the importance of abuse or trauma in shaping the course of people’s lives. There is growing literature to indicate that trauma is also linked with more severe psychiatric disturbances, including symptoms indicative of psychosis in general and schizophrenia in particular. Several lines of evidence suggest an association between trauma and psychosis with a dose-response effect. First, studies have demonstrated a high incidence of trauma in the lifetimes of patients with psychosis. Abused patients are particularly likely to experience positive symptoms, such as paranoid ideation, thought insertion, visual hallucinations, ideas of reading someone else’s mind, ideas of reference, and hearing voices making comments. Secondly, it has been suggested that of all diagnostic categories, psychosis displays the strongest association with child abuse. Thirdly, according to some researchers childhood sexual abuse is the most powerful predictor of later psychiatric symptoms and disorders after controlling for significant demographic variables. It has been suggested that the experience of abuse may create a biological or psychological vulnerability for the development of psychotic symptoms, including sub-clinical psychotic experiences such as low-grade delusional ideation, suicidal thinking and isolated auditory hallucinations. Exposure to psychological trauma worsens the prognosis of expression of psychosis, in terms of greater likelihood of transition to a more severe psychotic state. According to recent cognitive models of psychosis early adverse experiences such as social marginalization, childhood loss or severe childhood trauma may create an enduring cognitive vulnerability characterized by less subjective control over these experiences, negative schematic models of the self and a world that facilitates external attributions. This tendency to externally attribute events may lie beneath paranoid ideation. Current ideas about biological consequences of early adversities lend even more credibility to the notion of an enduring psychological vulnerability. It has been suggested that adverse life events or significant losses might be able to mould the neurodevelopmental abnormalities that underlie sensitivity to stressors, if they occur early enough or are sufficiently severe. Thus abnormal neurodevelopmental processes may originate from traumatic events in childhood. Specifically, when exposure to stressors persists and heightened stress-

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S79 Abstracts of the Invited Speakers induced glucocorticoid release is chronic, permanent changes in the hypothalamic-pituitary-adrenal (HPA) axis may ensue. This may account for the dopaminergic abnormalities considered central to biological accounts of psychosis. Other researchers are also examining the role of dissociative processes, attachment styles, and trauma related cognitive biases to try to better understand precisely how childhood trauma can lead to psychosis later in life. Clinically it is imperative to routinely enquire about traumatic experiences to respond appropriately and to offer psychosocial treatments to those who report traumatic life events in the context of psychotic experiences. Key words: Trauma, psychotic disorders, schizophrenia

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S79-80

Relationship of sexual dysfunction with trauma

Murat Erdem

Gulhane Military Medical Faculty, Psychiatry Department, Ankara, Turkey E-mail: [email protected]

Exposure to sexual trauma in adulthood is perceived as helplessness and loss of control even if sexuality has been defined as a pleasant event before trauma. Feelings of guilt and shame occurring after trauma as well as secondary clinical pictures such as depression, post traumatic stress disorder, and alcoholism are major causes of sexual dysfunction. Also sexual abuse in childhood raises a sense of weakness and perception of inadequacy. These individuals are at risk of developing inappropriate sexual behaviors over time. Indulging in sexual behaviors and thoughts that are evaluate sexuality as a gift or privilege are precursors for these inappropriate behaviors. In addition, the stigmatization caused by feelings of shame and guilt in these children is another cause of sexual problems in the future. Childhood sexual trauma is associated with negative attitudes about sexuality, lack of sexual satisfaction, orgasmic failure, need for sexual therapy and low self-esteem about sexual attractiveness. Chronic pelvic pain is a significant clinical entity which causes sexual dysfunction in many ways. In studies, the rate of traumatic childhood sexual experiences was found to be over 60% in these patients (N. Leithner, 2006). The difference between patients with chronic pelvic pain and a healthy control group was found to be even greater in terms of the increasing violence of sexual trauma. In a study of 63 patients with chronic pelvic pain, a history of sexual trauma was identified in 64.5% of cases and deficiencies in sexual function were found to be associated with the level of depression in these patients (ME Randolph, 2006). There are several studies that show that physical and sexual trauma plays a role in the etiology of vaginismus. In a study comparing the childhood and adolescent sexual traumas of patients with vaginismus and dyspareunia and control groups -(each group consisting of 29 patients) childhood sexual trauma was found to be twice as high as the control group in the vaginismus group (Reissing ED, 2003). In the literature there are case reports suggesting that EMDR is effective in cases of vaginismus resulting from childhood sexual trauma. In studies evaluating the relationship between childhood sexual traumas and a specific sexual dysfunction, aand in studies examining sexual functioning in general, a strong relationship has been found between these two situations. Structural vulnerability and the severity of sexual trauma were also reported to affect this relationship. While childhood sexual trauma is associated with sexual stimulation disorder, orgasmic disorder, vaginismus, dyspareunia and emotional problems about sexuality (sexual guilt, sexual anxiety etc.) in most individuals, high-risk sexual behaviors, characterized by extreme preoccupation with sexuality and uncontrolled sexual relationships, are seen in fewer individuals. Sexual childhood trauma in men is being reported, recognized and treated less frequently than the actual prevalence. Sexual dysfunction in these individuals was reported to be seen at least five times more than people who have not been exposed to a trauma. In a study of 1793 individuals, exposure to sexual trauma before age 16 has been reported at more than 1/3 of women and about 1/6 of men. In both sexes, especially in women, an association between the presence of childhood sexual trauma and sexual dysfunction has been identified (Najma JM, 2005). Leonard et al. found that problems associated with orgasm are the most frequent sexual problems seen in individuals who were exposed to a childhood sexual trauma (2008). Key words: Trauma, sexual dysfunction

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S80

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[PS-15] Symposium Title: Depression and pain Impact of pain on treatment in depression

Cengiz Akkaya

Departments of Psychiatry, Uludag University, Bursa, Turkey E-mail: [email protected]

Major depressive disorder (MDD) is a chronic, disabling condition with a wide range of symptoms, including core mood symptoms of depression and anxiety, cognitive and behavioral deficits, and somatic/physical disturbances. Approximately two-thirds of patients with depression experience physical pain symptoms (e.g. headache, neck and back pain, abdominal pain, diffuse musculoskeletal pain). Pain as a symptom of depression, often has a negative impact upon other depressive symptoms (for example, it may induce or exacerbate low energy, sleep disturbance, and anxiety), adherence to medication, and obtaining adequate therapy. Therefore, pain influences both the course of depressive illness and the treatment outcome. Also the severity of pain is found to be a strong predictor of poor response and health-related quality of life. Impairments in social and occupational functioning may increase when depression and pain coexist. Patients who fail to achieve remission after antidepressant therapy are more likely to suffer residual pain and other physical symptoms compared with remitted patients. The close relationship between pain and depression, and the growing evidence of a connection between treatment outcomes in these conditions, suggests that maximal patient benefit may result from treatments which effectively address both emotional and physical symptom domains. Therefore, treatments that address both depression and pain are highly desirable. Neurobiological evidence suggests that mood and chronic pain are connected via serotonin and noradrenaline neurotransmitter pathways. Serotonin and norepinephrine play a key modulating role in pain mechanisms in the central nervous system. Serotonin modulates both descending inhibitory and facilitatory pathways and thus exerts both an antinociceptive and a pronociceptive effect. Noradrenaline, however, typically acts centrally in an antinociceptive manner, exerting its effects via a-2-adrenoreceptors in the descending antinociceptive pathways. Efficacy for treating pain is best established for tricyclic antidepressants. But through the last decade, antidepressant medications, particularly selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs), are widely used in the management of MDD. SSRIs are often favored in practice because of their tolerability and safety. However, their efficacy in pain is thought to be relatively weak. On the other hand the mechanism of SNRIs has been hypothesized to confer analgesic effects independent of antidepressant action. Evidence suggests that potentiation of both serotonin and norepinephrine is required for effective analgesia; drugs that inhibit only one of these systems (particularly serotonin) appear to have a limited effect. Whether antidepressants relieve pain through direct analgesic effects or indirectly through antidepressant action is still under discussion. There may be a close association between analgesic and antidepressant effects and pain relief may be secondary to mood improvement. Key words: Pain, depression, antidepressant

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S81

Clinical characteristics and mechanism of pain in depression

Selçuk Kırlı

Department of Psychiatry, Uludag University, Bursa, Turkey E-mail: [email protected]

Although there is a large amount of data indicating that depression and pain symptoms are closely interrelated, they are not included in depression symptoms in the classification systems. Even so, new developments in neuroscience have carried the data on this interrelation and co-occurrence beyond the epidemiological dimension to the awareness of a common underlying mechanism (1,2). Although such a co-occurrence and the mechanisms that influence it are being discussed more and more, pain symptoms still cannot be well assessed or monitored and they are usually described by terms such as ‘medically unexplainable’, ‘functional’ or ‘psychosomatic’. The following statements may be made about the clinical characteristics of the symptoms (1): • They do not conform to the anatomic localizations which would help explain their causes. • They may vary in severity and location.

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• Pain symptoms occur in 1/5 – 1/3 of patients with depression. These ratios are approximately 4 times higher than the ratios of those with no depression. The ratios in the literature about pain symptoms in patients with depression are approximately 65% on average (3). • Chronic pain is a significant individual risk factor for suicide and self-injury. • Chronic pain results in increases in treatment costs and a poorer outcome. • The presence of pain as a residual symptom is the strongest predictor of recurrence. It should be kept in mind that chronic pain, which is considered as being ‘functional’ in terms of the mechanisms involved in having pain during depression, is medically unexpected, self-generated and associated with vulnerability to pain. Therefore, central factors should play a leading role in experiencing it (4). Living with pain causes negative emotions, but beyond that, continuous pain is a physical symptom of depression. A neurobiological explanation of experiencing these two situations concurrently is not all that difficult when the broadness and diversity of the mechanisms involved in experiencing depression are taken into consideration (5). The mechanisms involved in this co-occurrence may be summarized as follows: • The connection between the emotional and somatic (e.g. pain) symptoms of depression is probably set up through the HPA axis. This system plays an important function in vulnerability to stress. • The changes that emerge in the transfer of NA and 5HT in the CNS are of critical significance in terms of both depression and chronic pain pathophysiology (6). Monoamines regulate both mood symptoms and sensations of pain. • Pain stimuli are carried from the periphery to the CNS by primary afferent fibers and are regulated by stimulating glutamate and suppressor GABA. • The sub-cortical areas involved are the hypothalamus, periaqueductal gray matter, raphe dorsalis and locus coeruleus. These areas are also regulated by 5HT and NA. • Cortical processing of a pain sensation is carried out in the relevant areas of the cortex. In conclusion, it is obvious that common pathophysiological processes underlie the co-occurrence of depression and somatic pain symptoms seen in this picture and it is important to take such pain symptoms into consideration in a comprehensive treatment approach. Key words: Pain, depression, clinical characteristics

References: 1. Peveler R, Katona C, Wessley S, Dowrick C: Painfull symptoms in depression: under-recognized and under treatment. British J Psychiatry 2006;188:202-203. 2. Von Knorring L, Ekselius L: Idiopatic pain and depression. Quality of Life Research 1994;3:557-568. 3. Bair MJ, Robinson RL, Katon W, Kroenke K: Depression and pain comorbidity. A literatüre rewiev. Arch Gen Psychiatry 2003;163:2433-2445. 4. Mohr P, Bitter I, Svestka J, Seifritz E, Karamustafalıoğlu O, Koponen H, Sartorius N: Management of depression in the presence of pain symptoms. Psychiatria Danubina 2010;22:4-13. 5. Nemeroff CB, Vale WW: The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry 2005;66 (suppl. 7):5-13. 6. Wise TN, Fishbain DA, Holder-Perkins V: Painfull physical symptoms in depression: a clinical challenge. Pain Med 2007;8 (suppl. 2):75-82.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S81-2

[PS-16] Symposium Title: Marijuana; from mellow to madness Effect of cannabis use on cognitive functions

Cüneyt Evren

Bakirköy Training and Research Hospital for Psychiatry, Neurology, and Neurosurgery AMATEM, İstanbul, Turkey E-mail: [email protected]

If we look at the data of recent years, probation admissions to AMATEM Istanbul, which are mostly related to cannabis use, have increased significantly; the number of first admissions/number of control admissions for 2008, 2009 and 2010 are 2318/24261, 3759/31862 and 5639/30959, respectively. As for other psychoactive substances, the negative effects of cannabis use on cognitive functions are well known. Some cannabis-related cognitive function deficits improve after cessation of cannabis use, but growing evidence also suggests that other deficits persist after cannabis is discontinued and may hinder an individual’s ability to make the best use of behavioral therapies, putting him or her at greater risk for relapse of cannabis use (1). Cannabis seems to continue to exert impairing effects in executive functions even after 3 weeks of abstinence and beyond. Although basic attentional and working memory abilities are largely restored, most enduring and detectable deficits are seen in decision-making,

S82 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers concept formation, and planning. Those subjects reporting chronic, heavy cannabis use show the most enduring deficits (2). One can suggest that some of these impairments are not completely reversible upon cessation of cannabis use and moreover may interfere with the treatment of cannabis addiction. Therefore, targeting cognitive impairment associated with chronic cannabis use may be a promising novel strategy for the treatment of cannabis addiction (3). While acute administration of cannabis to patients with schizophrenia exacerbates symptoms and cognitive impairments and may have enduring effects, cannabis has also been found to have some beneficial effects on cognition, at least in certain subgroups of patients (4). Cannabis using patients had better attention and executive functions than non-cannabis using patients at baseline and after one year of treatment in a representative sample of first-episode schizophrenia patients. Cannabis using patients appear to comprise a subgroup of patients with better premorbid adjustment and premorbid frontal cognitive functions (5). Thus, while cannabis use is traditionally associated with cognitive impairment, the relationship is more complex in the case of schizophrenia. Key words: Cannabis, cognitive functions

References: 1. Blume AW, Marlatt GA. The role of executive cognitive functions in changing substance use: what we know and what we need to know. Ann Behav Med 2009; 37:117-25. 2. Crean RD, Tapert SF, Minassian A, Macdonald K, Crane NA, Mason BJ. Effects of chronic, heavy cannabis use on executive functions. J Addict Med 2011; 5:9-15. 3. Sofuoglu M, Sugarman DE, Carroll KM. Cognitive function as an emerging treatment target for marijuana addiction. Exp Clin Psychopharmacol 2010; 18:109-19. 4. Yücel M, Bora E, Lubman DI, Solowij N, Brewer WJ, Cotton SM, Conus P, Takagi MJ, Fornito A, Wood SJ, McGorry PD, Pantelis C. The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample. Schizophr Bull 2010 (In press) 5. Rodríguez-Sánchez JM, Ayesa-Arriola R, Mata I, Moreno-Calle T, Perez-Iglesias R, González-Blanch C, Periañez JA, Vazquez-Barquero JL, Crespo-Facorro B. Cannabis use and cognitive functioning in first-episode schizophrenia patients. Schizophr Res 2010;124:142-51.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S82-3

The differences between marijuana psychosis and other substance induced psychoses

Mükerrem Güven

Akdeniz University Research and Practice Center for Alcohol and Substance Addiction, Antalya,Turkey E-mail: [email protected]

Psychosis may be observed in intoxication from cannabis, alcohol, opiates, inhalants, stimulants, amphetamines, hallucinogens, phencyclidine, anxiolytics, sedatives and hypnotics. The condition of psychosis may also occur due to abstinence from alcohol, anxiolytics, sedatives, and hypnotics (1). Although mostly alcohol-dependent psychotic disorders are reported, the cannabis-psychosis relationship arouses more interest among researchers. Hypomania and agitation are more frequently noted in cannabis users compared with users receiving other substances. The symptoms of cannabis-psychosis usually disappear with a decrease in cannabis use, but the true nature of perception (flashbacks) hallucinations may be re-lived. As distinct from psychosis depending on other substances, evidence regarding the relationship between cannabis usage and the first attack of schizophrenia is increasing (2). There are long-term clinical follow-up studies to distinguish the acute toxic psychosis revealed in cannabis users from psychoses similar to schizophrenia, and also some studies conducted on the assumption that “cannabis psychosis” is distinct from other psychoses caused by other substances. Auditory hallucinations and emotional blunting are reported less commonly in cannabis psychosis compared to non-substance dependent psychoses. In a study investigating cannabis-induced psychoses, no significant relationship was determined between usage and the onset age of receiving cannabis; however, it has been put forth that a relation exists between cannabis use, the length of addiction and the quality and amount of cannabis received (3). Capsi et al. have reported that the risk for cannabis-induced psychosis is high in people carrying the valine-158 allele of the catechol-O-methyltransferase (COMT) gene (2005). Abuse substances affect different neurotransmitters in the central nervous system (4). Positive psychotic symptoms such as paranoid delusions and hallucinations are observed in half of cocaine addicts. As the period of cocaine use increases, negative symptoms and paranoid psychosis can be recorded. Stimulants such as cocaine and amphetamine can reveal psychosis by increasing dopaminergic activity in the central nervous system (CNS). -1 (CB-1) receptors are responsible for the effects of cannabis in the CNS. In the lateral putamen, pallidum and substantia nigra, CB-1 receptors are determined to be present in a high degree. Many neurotransmitter systems taking part in the etiology of schizophrenia, especially glutamatergic and dopaminergic systems, are affected by activation of the CB-1 receptor (5). Effects of substances on neurotransmission should be better investigated to understand how substance-induced psychotic disorder develops. Key words: Addiction, cannabis, psychosis, substance abuse

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References: 1. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA. 2. Van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002;15:319-327. 3. Makkos Z, Fejes L, Inczedy-Farkas G, Kassai-Farkas A, Faludi G, Lazary J. Clinical characteristics of cannabis-induced schizophrenia spectrum disorder. Neuropsychopharmacol Hung. 2011 Sep;13(3):127-38. 4. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005; 15;57(10):1117-7. 5. Müller-Vahl KR, Emrich HM. Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother. 2008 Jul;8(7):1037-48. Review.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S83-4

Selective serotonin reuptake inhibitors in the treatement of cannabis dependence

Musa Tosun

Istanbul Universit Cerrahpasa Medical Faculty, Department of Psychiatry, İstanbul, Turkey E-mail: [email protected]

Treatment of cannabis dependence should aim cannabis abstinence and psychosocial support as in general dependency treatment approach. The cannabis detoxification of the patient might be achieved by treatment interventions in hospital setting or following up the patient closely in outpatient setting. In outpatient setting, the regular urinalyses and close monitoring of the patient must be carried out. The metabolites of the cannabinoids could be detected in urinalysis from 3 days up to 4 weeks following the last use. Individual, family, and group psychotherapies might be beneficial while supporting the patient. Education is the most important element for both “abstinence” and “support programs,” as the motivation to quit and not to restart is primarily due to education on the effects and harmful consequences of cannabis abuse. Tranquilizer drugs might be efficient in short term withdrawal symptoms that might be seen in cannabis abusers or addicts. Selective serotonin reuptake inhibitors (SSRIs) as other antidepressant agents may be used in the treatment of depressive patients, who use cannabis as a self treatment for depression, and in co-morbid depression of cannabis use disorders or in depressive symptoms caused by cannabis abuse. In addition, SSRIs might also be used in the treatment of cannabis-induced anxiety disorders. There is growing interest in the use of antidepressants in cannabis abuse because of highly reported depression rates during the treatment of cannabis abuse or after the cessation. Nevertheless, there is a dearth of knowledge about the treatment of cannabis abuse with SSRIs. In a double blind placebo controlled study, fluoxetine has been reported to decrease the frequency of cannabis use in alcoholic patients with depression.

References:

1. Cornelius JR Salloum IM, Haskett RF, Ehler JG, Jarrett PJ, Thase ME, Perel JM. Fluoxetine versus placebo for the marijuana use of depressed alcoholics. Addict Behav. 1999 Jan-Feb;24(1):111-4. 2. Hall W. & Degenhardt L. : Cannabis-Related Disorders. in Kaplan & Sadock’s Comprehensive Textbook of Psychiatry 8th ed. Lippincott Williams & Wilkins, Philadelphia, 2005. Vol. I: 1211-1220 3. Tosun M. : Alkol ve Diğer Maddeler ile İlişkili Bozukluklar. İ.Ü.Cer.Paş.Tıp Fak. Yayınları, Rektörlük Yay.No: 4215, Fak.Yay.No. 229, İstanbul, 2000 : 96-100.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S84

S84 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

[PS-17] Symposium Title: Overcoming treatment resistance: An update Treatment strategies for treatment resistant depression

Selçuk Aslan

Gazi University, Medical School, Psychiatry Department, Ankara, Turkey E-mail: [email protected]

Depression is a disorder with heterogenic etiology and variable clinical features. Response to the treatment is defined as a 50% reduction in admission symptoms. Recent studies with large numbers of patients have revealed that acute phase treatment should last for 6 weeks, including at least 4 weeks with effective dosages. Approximately 60% of patients have a response to the first antidepressant treatment. The remainder, 40% of patients, either has a partial response or they are non-responders (Fava 1996). At the end of 6 weeks with optimum treatment dosing, if symptoms have not reduced by 20-25%, patients are described as non- responders and drug treatment should be switched to another type of antidepressant medication. Patients, who do not respond to trials of adequate dosages and periods of two or more different classes of antidepressant treatments, are considered as treatment- resistant depression (TRD). If there is a partial response to antidepressant treatment, waiting for couple of weeks is the rational approach. The patients who have high depression scores at the initial evaluation have relatively higher degrees of partial or non-response to antidepressant medications. These cases are more likely to have comorbid axis 1 and axis 3 physical disorders. An 8-12 week period of effective antidepressant treatment should be applied in these cases. Thase and Rush, proposed 5-stage-model for the description of TRD (1997). Later in the STAR D study, Rush et al. developed sequences of treatment alternatives for relieving depression (Rush et al. 2003). On the other hand, increasing drug dosages results in more side effects and adverse reactions. Some patients may be low metabolizers and higher doses may result in significant side effects. Also fast metabolizer patients may respond to higher doses of medications. Efficacy of atypical antipsychotics, stimulants, pindolol, lithium, and lamotrigine have been tested for augmentation in ongoing treatment for TRD in clinical trials (Caravalho et al 2009). In severe cases with no response or partial response to treatment, inpatient treatment should be considered. Non-responders or partial responders can be treated with electro convulsive therapy with anesthesia or non-responders can be treated with rTMS (Paul et al 2006). Selected non-responsive cases may be treated with more invasive techniques such as deep brain stimulation or vagus nerve stimulation. Biological predictors should be identified to irecognize patients who will not respond to two adequate trials of different antidepressant. In addition, psychotherapeutic interventions during the treatment period, such as observing and revealing automatic thoughts, assumptions, and basic beliefs and depressive schemas, should be evaluated and behavioral and cognitive interventions can be applied. Activity scheduling and participating in regular exercise might also be helpful to some degree. Key words: Depression, treatment resistant depression

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S85

Treatment resistant psychiatric disorders and trauma history

Mehmet Akif Ersoy

Ege University School of Medicine, Department of Psychiatry, Izmir, Turkey E-mail: [email protected]

Although many clinicians depending on their experience will agree that childhood trauma history will cause treatment resistance regardless of the diagnosis, studies investigating this issue directly are scarce. During our search of literature we have found publications on the relationship between childhood trauma and treatment resistance in a few disorders such as obsessive compulsive disorder (OCD), major depression, and bipolar affective disorder. One study reported that 82% of OCD cases had a history of childhood trauma. In this study 39% of the cases met the criteria for post traumatic stress disorder (PTSD) and half of those who had a history of trauma met the PTSD criteria. It is noticeable that those who had major depression or borderline personality disorder, in addition to OCD, had a higher risk of having comorbid PTSD. Treatment resistant OCD cases should be screened for PTSD and having comorbid major depression and/ or borderline personality disorder helps to predict PTSD and may help to determine the severity of the illness.

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An indirect approach is looking for comorbidity of trauma related disorders in treatment resistant cases. One study has pointed out that OCD cases with comorbid PTSD have worse treatment outcomes. A meta-analysis study has revealed that childhood trauma not only effects lifetime risk of major depression, it also negatively effects severity of clinical parameters and results of treatment. This particular study, which included 16 epidemiological studies (23544 cases), showed that childhood abuse is related to recurrent and persistent depressive episodes. Another meta-analysis of 10 clinical studies with a total of 3098 cases, found that childhood abuse is related to absence of remission and absence of treatment response in depression. In bipolar disorder, those who have had childhood trauma, had earlier onset of illness, more severe current symptoms of mania or depression and more frequent episodes of depression. Half of adult bipolar disorder patients were found to have severe childhood trauma. In patients with early childhood trauma such as early loss of parents and physical or sexual abuse or neglect, psychotherapy alone had favorable results compared to monotherapy of antidepressants, while interestingly combination of psychotherapy and pharmacotherapy was slightly more effective than psychotherapy alone. Researchers have stressed that psychotherapy must be included in the treatment of chronic depression patients with childhood trauma. Studies which directly investigate the relationship of treatment resistance and childhood trauma are scarce. Some comorbid conditions, such as personality disorders, that complicate treatment of depression are known to be related to childhood trauma. As a result, we can with great confidence state that childhood trauma is related to treatment resistance in most psychiatric conditions. Especially in cases of treatment resistance, childhood trauma should be investigated and appropriate treatment modalities should be added to the treatment regime. Key words: Treatment resistance, childhood trauma

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S85-6

Pyshosocial approaches for treatment resistant symptoms in patients with schizophrenia

Mustafa Yıldız

Kocaeli University School of Medicine, Department of Psychiatry, Kocaeli, Turkey E-mail: [email protected]

One of the main goals in the treatment of schizophrenia is to increase psychosocial functioning and to provide a satisfying life for patients with schizophrenia who have persistent symptoms although all treatment efforts, including ECT, had been performed. Whatever the clinical conditions of the patients are, they have a right to live in dignity in their community like other people. The emphasis in psychiatric rehabilitation approaches is on enhancing psychosocial functioning and quality of life of patients. Increasing the functioning of patients depends on controlling symptoms as much as possible and preventing exacerbations. Patients should learn and practice coping skills (humming or singing, reading aloud, thinking “stop”, listening to the radio, watching TV, doing favorite hobbies, telling the voices to go away, doing physical exercise, going to movies etc.) for their persistent symptoms. Sometimes it may be necessary to use behavioral techniques; for example, a patient showing 20 aggressive behaviors due to command hallucinations a week, showed on aggressive behavior a month after applying a behavior modification program. Patients should be placed in a program, in which their healthy aspects can be developed and keep them in continuing daily activities, so that they become empowered. All these results can take place by collaboration and coordination of different services. Being provided a safe environment, getting positive feedback, participating in occupational activities and working in a less stimulating milieu are also important for patients. It could be possible for patients to live a more satisfying and more normal life by integrating treatment and rehabilitation services. The elements of integrated approaches are: patients’ participation in treatment and the maintenance of treatment, development of treatment alliances, teaching illness management, using cognitive behavioral treatment methods, modifying new resources to attain personal goals, accommodating community resources, establishing relationships with psychosocial clubs, involving families in the treatment, and providing personal support services (case management), supported employment, supported residence, and peer supports. Key words: Schizophrenia, persistent symptoms, functioning, rehabilitation

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S86

S86 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

[PS-18] Symposium Title: Chronobiotics and chronotherapeutics in psychiatry The use of sleep deprivation in the treatment of depressive disorders

Adem Aydın

Department of Psychiatry, Yuzuncu Yıl University, Van, Turkey E-mail: [email protected]

Sleep deprivation has been used for exploring functions of sleep among healthy individuals and for treating patients suffering from depressive symptoms. Sleep deprivation is a rapid, effective and brief therapeutic alternative. Two types of sleep deprivation applications have been implemented; one is deprivation of sleep for whole night and the other is partial deprivation of sleep in the second part of the night. Although various hypotheses have been developed pertaining to the treatment potential of sleep deprivation in depression, the mechanisms underlying the process are still obscure (1). Early systematic research conducted by Pflug and Tolle proposed that patients characterized by endogenous depressive symptoms receptive to sleep deprivation have deficits in their circadian systems and sleep deprivation aids at ameliorating the dysregulation in the biological rhythm (2). Sleep deprivation and REM sleep deprivation act like antidepressants and some antidepressants have suppressing effects on REM sleep. Hence the role of REM sleep on the development of depression has received more attention. The reduction of REM latency and REM intensity are prominent features in patients with depression. Sleep deprivation reverses these two effects (3). The psychological response to sleep deprivation seems to occur regardless of diagnostic category such as endogenous-reactive, psychotic, nonpsychotic, unipolar, bipolar, schizoaffective, or seasonal (4). Merely diurnal variation (soothing of affect is typical in patients with depression in the later hours of daytime) and chronobiological differences are substantial in the psychological response to sleep deprivation (5). About 50-60 percent of patients with depression are prone to reflect antidepressant influences after one-night of sleep deprivation therapy. Deceleration in symptom severity as well as amelioration in suicidal thoughts occurs. The temporary antidepressant influence of the initial application does not predict inadequacy of further applications. If applications of sleep deprivation are continued one or two times per week, it has been claimed that it is likely to provide effective prophylaxis (6). Although sleep deprivation provides a rapid psychological response and a potent influence, its application is not prominent in major depression. Sleep deprivation can be qualified as an awkward method, because the application requires constant monitoring and to ensure wakefulness of patients as well as carrying a relapse risk in fiesta. The most prominent advantage of sleep deprivation compared to other medications and ECT is that it causes rapid and apparent improvement in affect. Therefore the pros and cons of sleep deprivation should be taken into account in treatment planning. Key words: Depression, sleep deprivation, treatment

References: 1. Rechtschaffen A. Current perspectives on the function of sleep. Perspect Biol Med 1998;41:359-390. 2. Pflug B, Tolle R. Disturbance of the 24 hour rhythm in endogenous depression and treatment of endogenous depression by sleep deprivation. Int Pharmacopsychiatry 1971;6:187-196. 3. Giedke H, Schwarzler F. Therapeutic use of sleep deprivation in depression. Sleep Med Rev 2002;6:361–377. 4. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol 2006;21:11-5. 5. Selvi Y, Gulec M, Agargun MY, Besiroglu L. Mood changes after sleep deprivation in morningness–eveningness chronotypes in healthy individuals. J Sleep Res 2007;16:241–4. 6. Hemmeter UM, Hemmeter-Spernal J, Krieg JC. Sleep deprivation in depression. Expert Rev Neurother 2010;10(7):1101-15.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S87

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S87 Abstracts of the Invited Speakers

Psychotropic drugs effecting biological rhythm (Chronobiotics)

Elif Oral

Department of Psychiatry, Faculty of Medicine, Atatürk University, Erzurum, Turkey E-mail: [email protected]

Biological clocks such as circadian, ultradian, and infradian rhythms have their own organizations, independently from environmental conditions. Although there is biological sustainability, psychiatric disorders and also psychotropic medications have important effects on the synchronization of biological clocks. Various biological mediators such as glutamate, γ aminobutyric acid, histamine, dopamine, acetylcholine, serotonin and their receptor systems take on the mediation of inner clocks via psychotropic drugs. Histaminergic activity is highly increased during wakefulness. H1 antagonists, generally increase Slow-Wave Sleep and stage 2 sleep and reduce rapid eye movement sleep. Diphenhydramine can cause subjective sedation and decreased sleep latency with no effect on memory or learning processes. The long elimination half-lives of these drugs can result in next-day sedation and impairment of psychomotor and cognitive function the next morning. Benzodiazepines shorten sleep-onset latency, increase total sleep time and stage 2 sleep, and suppress rapid eye movement sleep and slow-wave sleep. The risk of rebound insomnia is greatest with rapid elimination of benzodiazepines. About 65% of major depressive disorder patients report sleep complaints. Based on polysomnography studies, sleep architecture is estimated to be disturbed in up to 90% of depressed patients. Except desipramine, all TCAs block H1 and α1 receptors to varying degrees. As a general rule, the noradrenergic TCAs (e.g. desipramine, protriptyline) are considered ‘activating’. These agents have a tendency to increase sleep-onset latency as well as to decrease total sleep time, associated with an increase in wake time after sleep onset. Paroxetine and fluoxetine clearly suppress REM sleep, both among healthy volunteers and depressed patients. Compared to other SSRIs, citalopram may be less activating and therefore less likely to disrupt sleep continuity. Lithium and valproate have many acute, subacute, and chronic effects on systems, at the cellular and molecular levels. Lithium treatment modifies circadian rhythms in humans and in most animals, primarily by lengthening the period of the cycle. Most of the sleep-promoting effects of antipsychotic drugs have been related to their potency to antagonize α , histaminergic, or cholinergic neurotransmission. Among classical antipsychotics, drugs having these properties, such as phenothiazines and thioxanthenes, are clearly sedative and promote sleep. Among atypical antipsychotics, drugs having this pharmacodynamics profile are olanzapine, clozapine, and quetiapine. Clozapine and olanzapine increase total sleep time and sleep efficiency and have no clear-cut effect on REM sleep. Key words: Psychotropic drugs, biological rhythm

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S88

A general overview of chronotherapeutics

Yavuz Selvi

Department of Psychiatry, Yuzuncu Yil University, Van, Turkey E-mail: [email protected]

The sleep-wake cycle occurs because of the two independent but additive processes, homeostatic sleep and circadian processes. Circadian rhythms play a significant role in regulating daily behavioral rhythms, cortisol and melatonin secretions, body temperature, sleep/wake cycle, alertness and performance levels. Disrupted synchronization of circadian rhythms impairs cognition, behavior and mood with deterioration of sleep-wake cycle and social rhythms. Some clinical and neurobiological findings suggest circadian dysregulation in depressive patients. Diurnal variation of mood, early morning awakening, phase advance for body temperature, cortisol, latency of the first phase of REM sleep for several other hormones and monoamines or their metabolites and sleep disturbances are core features of depression that have linked depression with circadian rhythm function (1,2). Clinical and neurobiological findings have promoted the idea that the restoration of circadian rhythm could have an antidepressant effect. The term, chronotherapeutics, refers to biologically-based, non-pharmaceutical and clinical interventions that act on disrupted biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions (3). Delayed therapeutic effects, tolerability, side effects, and drug–drug interactions of pharmacotherapeutic agents, as well as pregnancy and the postpartum period, prevent antidepressant use and promote chronotherapeutic interventions.

S88 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Chronotherapeutics are applied effectively in endogenous, reactive, unipolar, bipolar, schizoaffective depression, depression in the elderly, secondary depression, depression in pregnancy and postpartum depression. The target of chronotherapeutic interventions, as in antidepressant drug treatments, is to modulate the same neurotransmitter systems (5-HT, NA, DA), the same brain structures, and the same clinical symptoms and findings more rapidly and with fewer side effects. These interventions include wake therapy (the use of prolonged periods of wakefulness; partial or total sleep deprivation), shifting of sleep time (sleep phase advance therapy; stepwise shift forward of the sleep-wake cycle to the early evening); bright light therapy in correct time and sufficient dose, and dark or rest therapy for bipolar mania and rapid cycling patients. When the therapeutic effects are transient, different chronotherapeutic interventions can be combined to maximize antidepressant response and prevent relapse. Psychiatrists should consider chronotherapeutic interventions as strong and safe treatment approaches (3,4). Key words: Biological rhythm, chronotherapeutics, mood, sleep, sleep deprivation

References: 1. Lack LC, Wright HR. Chronobiology of sleep in humans. Cell Mol Life Sci. 2007; 64(10):1205-15. 2. Selvi Y, Besiroglu L, Aydin A. Chronobiology and Mood Disorders. Current Approaches in Psychiatry 2011; 3(3):368-386. 3. Benedetti F, Barbini B, Colombo C. Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11(6):509-22. 4. Hajak G, Landgrebe M. Time and depression: when the internal clock does not work. Medicographia. 2010;32:146-151.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S88-9

Bright light therapy in treatment of depressive disorders other than seasonal affective disorder

Mustafa Güleç

Department of Psychiatry, Ataturk University, Erzurum, Turkey E-mail: [email protected]

Studies of light therapy for non-seasonal depression have a history at least as long as studies of seasonal affective disorder (SAD), but on the whole the results have been less clear-cut (Tuunainen et al., 2005). The APA work group found, within its selection, positive evidence for efficacy except when light therapy and medication were combined (Golden et al., 2005). Studies completed by the time of the present congress clearly would have reversed that conclusion (Benedetti et al., 2003; Martiny, 2004; Terman, 2006). The strategy has been recommended by the Committee on Chronotherapeutics of the International Society for Affective Disorders (Wirz-Justice et al., 2005) and in an international response (Wirz-Justice et al., 2004) to a review of new antidepressants that overlooked light therapy, published in Science (Wirz-Justice et al., 2004). A difficulty with most non-seasonal studies has been their inability to confront the early hypothesis that light therapy is specifically tuned to patients with SAD as a countermeasure to long winter nights. Seasonality lies on a continuous dimension from noticeable (but not disturbing) to mildly, moderately and severely disturbing (Terman, 1988). SAD falls into the latter category, with major depressive episodes restricted to winter. In a far larger number of cases, recurrent or chronic depressions are exacerbated in winter but can occur at any time of year. Such patients provide moderate global seasonality scores (Rosenthal et al., 1987) in comparison to higher scores for SAD. Thus, patients with non-seasonal depressions can still show seasonality, which might be the key to their response to light therapy. Subsequent to the aforementioned inconclusive meta-analysis of light therapy for non-seasonal depression (Tuunainen et al., 2005), some researchers conducted an investigation to clarify this issue with a patient sample in which depression was chronic and without any seasonal modulation (Goel et al., 2005). Under morning light therapy, the proportion of subjects with depression rating scale improvement of 50% or more was 0.60 vs. 0.10 for the low-output negative air ionizer placebo. Moreover, there are also very recent reports claiming that bright light therapy alone is effective in some patient groups with non-seasonal major depression (Kripke, 2011a; Kripke, 2011b; Martiny, 2011). Now, we can begin to surmise that light therapy for seasonal and non-seasonal depression is equally effective. Perhaps the patients with non-seasonal depression are light deprived at any time of year, and this situation results in exacerbation of circadian rhythm phase delay, given the absence of the critical early morning light signal that synchronizes the internal clock to local time. Such delay may be depressogenic regardless of the season. However, the growing concern about medication side effects would seem to fit well for our old-new alternative (Terman, 2007). Key words: Seasonal affective disorder, non-seasonal affective disorder, depression, treatment, bright light

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S89

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S89 Abstracts of the Invited Speakers

[PS-19] Symposium Title: Are the effects of psychopharmacological and other therapeutic approaches neuroregenerative or neurodegenerative? Review of recent data Is the effect of psychotropic drugs neurodegenerative or neuroprotective?

Ömer Aydemir

Department of Psychiatry, Celal Bayar University, Manisa, Turkey E-mail: [email protected]

Various stress experiences affect gene expression of neurotrophic/growth factors in the hippocampus. Among the neurotrophic factors, brain-derived neurotrophic factor (BDNF) has the most prominent role. With the stress producing effects of early life traumas, the level of BDNF decreases and susceptibility to depression develops. Recurrent and insufficiently treated depressive episodes have further impact on decreased BDNF and increase neuronal atrophy. Decreased level of BDNF in patients with major depressive disorder has been demonstrated in many studies and BDNF levels increase after antidepressant treatment, along with symptom recovery, in comparison to those seen in healthy control subjects. This increase cannot be achieved in patients that do not respond to antidepressant treatment. The neuroprotective effect of antidepressants are mediated by mitogen activated protein kinases/extracellular regulated kinases (MAPK/ ERK) and wingless/glycogen synthase kinases (Wnt/GSK). In a meta-analysis, 23 studies were evaluated and data for 1504 patients were subjected to statistical analysis. The effect size was calculated as 0.62 (95% confidence interval: 0.36-0.88). As a result of meta-regression, the change in the level of serum BDNF after antidepressant treatment was independent of the change in depressive symptomatology, duration of treatment, and history of antidepressant use. As clinical improvement obtained with antidepressant treatment persists, the level of serum BDNF remains unchanged. Beside antidepressants, mood stabilizers, especially lithium have been studied with respect to neuroplasticity. Neuroprotective effects of mood stabilizers are mediated by increasing transcriptional activity of (cAMP response element binding protein) CREB, inhibiting GSK-3B and increasing the expression of BDNF. In studies both with lithium and valproate, increased cerebral grey matter volume was reported. In lithium studies increases in left anterior cingulate volume, right anterior cingulate volume, hippocampal volume and amygdala volume, and in valproate studies an increase in left anterior cingulate volume were found. Both mood stabilizers are associated with increased hippocampal N-acetyl aspartate level. Antipsychotic drugs do not have a group effect. While haloperidol does not have any effect on phosphorilated ERK (pERK), olanzapine increases it. Haloperidol also decreases the level of BDNF and is suggested to have neurotoxic effects. Among the other antipsychotics, clozapine, quetiapine and risperidone prevent cell death. It has been demonstrated that clozapine and quetiapine increase the level of BDNF. Quetiapine is suggested to increase proliferation of mature neurons, although there is no evidence that clozapine and olanzapine have the same effect. Key words: Psychotropic drugs, neuroplasticity, neurodegeneration, neuroprotective effect

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S90 Effect of psychotherapy on neurogenesis

Mine Özmen

Istanbul Universit Cerrahpasa Medical Faculty, Department of Psychiatry, İstanbul, Turkey E-mail: [email protected]

Adverse life experiences in childhood are considered to be associated with emotional and cognitive development as well as brain structure and functions. It is suggested that they might reduce neurogenesis, which in turn may cause memory, learning, functional stress response disturbances. It is known that hippocampal neurogenesis is affected by stress, hormones, aging, environment and activity. Exposure to acute or chronic stress may result in suppression of one or more phases of neurogenesis. In animal studies, reduction of neurogenesis in the caudal part of the hippocampus was shown after maternal separation of 3-weeks old rats. Although it was reported that the suppression was reversible after appropriate time and treatment in some studies, some other writers suggest that early life stress in the first 2 weeks can cause irreversible reduction in neurogenesis. Besides, there is an argument that neurogenesis can not increase by learning in the animals which were exposed to prenatal stress. One suggested reason for this lifetime persistency of reduced neurogenesis is that stress occurring in early childhood coincides with the development of dentate gyrus. It has been shown that corticosteroids

S90 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers inhibit neurogenesis in the hippocampus, subventricular zone and olfactory epithelium and this inhibition can remit by pharmacological treatments. There are case reports and studies with limited cases, which suggest that effective psychotherapy can reduce symptoms and this reduction can change the in the hypothalamic-pituitary axis. It may be hypothesized that in an effective psychotherapy process, coping with stress, new relationship experiences and learning can increase neurogenesis and this may be one of the mechanisms of effectiveness of psychotherapy. This hypothesis should be tested with animal and human studies in which neurobiology; psychiatry and neuroscience disciplines can interact and work together.

References: 1. Korosi A et al. Early-life stress mediated modulation of adult neurogenesis and behavior. Behav Brain Res. (2011) doi:10.1016/j.bbr.2011.07.037 2. McEven BS. Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann NY Acad Sci 2010 Sep;1204 Suppl:E38-59. 3. Miranda Olffa, Giel-Jan de Vriesa, Yener Guzelcana, Johanna Assiesc, Berthold P.R. Gersons. Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology (2007) 32, 619–626

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S90-1

Are the effects of psychopharmacological and other therapeutic approaches neuroregenerative or neurodegenerative? Review of recent data and effects of physical exercise

Hakan Balıbey

Ankara Military Hospital, Psychiatry Clinic, Ankara, Turkey E-mail: [email protected]

Research in humans and animals has shown that exercise improves mood and cognition. Physical activity has been consistently shown to be associated with improved physical health, life satisfaction, cognitive functioning, and psychological well-being. Conversely, physical inactivity appears to be associated with the development of psychological disorders. Physical activity also causes a robust increase in neurogenesis in the dentate gyrus of the hippocampus, an important brain area for learning and memory. The results of epidemiological studies (cross-sectional, prospective and retrospective) support a positive relationship between cognition and physical activities. They include supramolecular mechanisms (e.g. neurogenesis, synaptogenesis, and angiogenesis) which, are in turn controlled by molecular mechanisms, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), hormones and second messengers. An active lifestyle might prevent or delay loss of cognitive function with aging or neurodegenerative disease. Exercise could involve common cellular pathways important for neurogenesis, cell survival, synaptic plasticity and vascular function. Optimal maintenance of brain health might depend on exercise. The beneficial effects of exercise are likely to be mediated in part by hippocampal neurogenesis. Further investigation into the functional significance of neurogenesis, by designing behavioral tasks that are specific for the dentate gyrus, will help to determine the relative contribution of the new cells. Exercise influences brain vasculature. In particular, physical activity increases the proliferation of brain endothelial cells and angiogenesis throughout the brain. Growth factors such as insulin-like growth factor (IGF) and vascular endothelial growth factor (VEGF) play an important role in the angiogenic and neurogenic effects of exercise on the brain. The neurotrophin BDNF is considered to be the most important factor upregulated by physical activity because it has an important role in synaptic plasticity and cell genesis, growth and survival. Interestingly, there is a positive interaction between BDNF expression and serotonin. Serotonin receptor activation enhances BDNF expression in hippocampal cells, BDNF is recognized to be a key protein modulating brain plasticity and it is distributed widely throughout the brain. In humans, serum BDNF concentrations rise after exercise. The involvement of such pathways, particularly in the hippocampus, may in turn lead to an improvement in cognitive function, enhancement of psychological well-being, and a decrease in the risks of Alzheimer’s disease (AD) and dementia as well as decreases in symptoms of depression and anxiety. While intense exercise (as observed in conditions such as “excessive exercise” and “overtraining syndrome”) leads to a lessening of anxiety, these mood variations are more related to the construct of depression than to the construct of anxiety. Physiological effects of exercise and the benefits of exercise on psychiatric disorders will be discussed in the light of current literature in this presentation. Key words: Physical activity, exercise, BDNF, hippocampal neurogenesis, neuroregeneration, neurodegeneration, synaptic plasticity, cognition, mood

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References: 1. Lista I, Sorrentino G. Biological mechanisms of physical activity in preventing cognitive decline. Cell Mol Neurobiol. 2010;30(4):493-503. 2. van Praag H. Exercise and the brain: something to chew on. Trends Neurosci 2009;32(5 ):283–90. 3. Little Exercise, Big Effects: Reversing Aging and Infection-Induced Memory Deficits, and Underlying Processes. Barrientos R. M., Frank M.G, Crysdale N.Y, Chapman T.R, Ahrendsen J.T at all. The Journal of Neuroscience, 2011; 31(32):11578 –86. 4. Christofoletti G, Oliani M.M, Bucken L.T, Gobbi S, Beinotti F, Stella F. Physical activity attenuates neuropsychiatric disturbances and caregiver burden in patients with dementia. Clinics (Sao Paulo). 2011; 66(4): 613–8. 5. Ma Q. Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health. Neurosci Bull. 2008;24(4):265-70. 6. van Praag H. Neurogenesis and exercise: past and future directions. Neuromolecular Med. 2008;10(2):128-40. 7. Ang. ET, Tai YK, Lo SQ, Seet R, Soong TW.Neurodegenerative Diseases: Exercising Toward Neurogenesis and Neuroregeneration. Front Aging Neurosci. 2010; 2: 25. 8. Tomporowski P. D., Lambourne K., Okumura M. S. Physical activity interventions and children’s mental function: an introduction and overview. Prev Med. 2011; 52(Suppl 1): S3–S9. 9. Fadillioglu E., Kaya B., Uz E., Emre M.H., Ünal S. Effects of Moderate Exercise on Mild Depressive Mood, Antioxidants and Lipid Peroxidation. Bull Clin Psychopharmacol 2000; 10(4):194-200.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S91-2

[PS-20] Symposium Title: Controversial topics in eating disorders Comorbidities in eating disorders

Atila Erol

Sakarya University, School of Medicine, Department of Psychiatry, Sakarya, Turkey E-mail: [email protected]

Patients with eating disorders exhibit high rates of psychiatric comorbidity and the number of comorbid psychiatric disorders is high. The treatment of co-occurring psychiatric problems in eating disordered patients is essential for good clinical management and the outcome of treatments. Higher rates of comorbidity often mean greater severity, treatment resistance and poor outcomes in eating disorders. The most prevalent Axis I disorders seem to be mood and anxiety disorders, alcohol and substance abuse, and bipolar disorder. Axis II disorders are also common. At least 80% of anorexia nervosa (AN) or bulimia nervosa (BN) patients have at least one additional psychiatric disorder over their lifetime. Mood disorders are very common among patients with AN. Major depressive disorder occurs in 50-70% of AN patients. Bulimic patients have 52-75% affective disorder, with 63% having major depression. Lifetime prevalence rates of major depression in BN are 50-65%. Among study samples with restricting and binging /purging anorexia nervosa, prevalence rates of any anxiety disorder are found to be between 24% and 71%, respectively. Among patients with BN prevalence rates for any anxiety disorder, social phobia, generalised anxiety disoder (GAD) or panic disorder are reported to be 36%, 17%, 12% and 10% respectively. The approximate rates of any anxiety disorder in BN are reported to be between 57 and 75 %. Thirty-five percent of restricting AN patients have obsessive compulsive disorder (OCD) and binging/purging AN patients have 44% OCD. BN patients have comorbid OCD 40% of the time. Lifetime prevalence rates of substance abuse in AN ranged from 12% to 18% and in BN the rates ranged from 30% to 70%. The results of clinical studies indicate that patients with BPD have higher rates of eating disorders compared with the general population. Rates of lifetime BPD in eating disorders patients are variable but higher than rates of BPD in the general population. Among eating disorder patients post-traumatic stress disorder rates were found between 8% to 11%. Key words: Eating disorders, anorexia, bulimia, comorbidity

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S92

S92 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Psychopharmacological treatments in eating disorders

Alican Dalkilic

St. Elizabeths Hospital, Washington, DC 20032, USA E-mail: [email protected]

Pharmacological treatment options have limited evidence of benefit in treatment of eating disorders, yet a comprehensive psychiatric evaluation besides a physical exam and basic screening tests (complete blood count (CBC), basic metabolic panel, Mg, P, thyroid stimulating hormone (TSH), lipid panel, pregnancy test, urine analysis (UA), urine drug screen (UDS), ECG, and Dexa scan) should be conducted. Establishing a therapeutic alliance with empathy, positive regard, reassurance, and support (1) sets up the foundation for a successful treatment process. The patient’s safety should be evaluated with particular attention paid to suicidal ideation, plans, intentions, history of attempts and impulsive or compulsive self-harm behaviors. After assessing eating disorder symptoms, signs, and behaviors and the general medical condition of the patient a decision about treatment site (specialized inpatient unit, residential treatment or partial hospital program, intensive outpatient, or outpatient care) can be made. In eating disorders in general, but especially in adolescences with eating disorders, inclusion of the family and primary support group in the treatment process is essential. The treatment options and goals in eating disorders include nutritional rehabilitation, psychosocial interventions, medications, and other somatic treatments. Nutritional rehabilitation aims to restore weight, normalize eating patterns, achieve normal perception of hunger and satiety cues, and correct biological and psychological problems caused by malnutrition (1). Psychosocial interventions include individual and group based cognitive behavioral and interpersonal therapies, acceptance and mindfulness therapies, and psychodynamic approaches, as well as nutritional counseling, dialectical behavioral therapy (DBT), and family therapies. There are more therapies with specific names such as mealtime support and multifamily group therapy, but they use similar approaches to the previously mentioned ones. Although there is clinical evidence about use of antidepressants in treatment of eating disorders (especially SSRIs, calcium, vitamin D, and zinc and limited data about benzodiazepines, mood stabilizers, and atypical antipsychotics), so far only fluoxetine is approved for the treatment of bulimia nervosa by the Federal Drug Administration (FDA) 1,2). Sertraline has been found to be effective in a randomized and controlled trial, as well. Medications have not been proven to be more effective than psychosocial interventions in treatment of eating disorders so far. Some studies have found the combination of CBT with medication to be more effective. Topiramate has been found to be effective in some small controlled trials especially in reducing binging behavior, but due to potential side effects is should be reserved as a secondary medication (1,3). Topiramate or zonisamide are prescribed to target binging behavior and also for weight reducing effects in patients who may benefit from weight loss. Bright light therapy is another intervention demonstrated to decrease binge frequency in several controlled trials (1). Although clinicians are advised to use caution when prescribing medications to eating disorder patients due to potentially dangerous medical co-morbidities, some medications should be avoided or used only as last resorts. Bupropion is contraindicated in bulimia due to a heightened seizure risk (1,3). Medications that increase the risk of arrhythmia or prolong the QTc interval should be avoided or if they are used, adverse events should be monitored closely. Sibutramine was taken off the market in USA in 2010 due to cardiac adverse events. In addition, medications with a narrow therapeutic range such as lithium should be avoided. Benzodiazepines, especially the ones with high addiction potential, should not be used in patients with addiction risk. In clinical practice many eating disorder patients end up being on multiple medications due to high rates of co-morbidity with anxiety and mood disorders, substance abuse and dependence conditions, trauma related disorders, and personality disorders. Beside reviewing pharmacological treatment options in eating disorders we will also discuss the management of cases with co-morbid conditions. Key words: Eating disorders, pharmacology, pharmacotherapy, treatment, pharmacological treatment

References: 1. American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders Compendium. American Psychiatric Association 2006 1,612 pages ISBN 978-0-89042-385-1. 2. Pharmacotherapy of eating disorders. Jackson CW, Cates M, Lorenz R. Nutr Clin Pract. 2010 Apr;25(2):143-59. Review. 3. Psychopharmacology of eating disorders in children and adolescents. Golden NH, Attia E. Pediatr Clin North Am. 2011 Feb;58(1):121-38, xi. Review.

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Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S93 Abstracts of the Invited Speakers

Obesity and impulsivity

Bilge Burçak Annagür

Department of Psychiatry, Selcuk University, Selcuklu Medical School, Konya, Turkey E-mail: [email protected]

Obesity is not inlcuded in eating disorders characterized by the DSM-IV classification of the American Psychiatry Association. Current clinical diagnosis depends on body mass index (BMI). Although it was not evaluated among eating disorders, it presents psychological characteristics seen commonly in eating disorders. Characteristics related with eating disorders such as low self-esteem, body dissatisfaction, perfectionistic attitudes, impulsivity and disinhibition have also been observed in obese patients (1,2). Obese patients are divided into two subgroups, with or without binge eating disorder (BED). Body weights of subjects with binge eating disorder are related to their overeating and psychopathologies, especially depression, are more frequent compared to the other group. Aggressiveness and anger are involved in significant psychopathological characteristics common in patients with eating disorders (3). Some researchers suggested that impaired eating behavior is related to low self-esteem and high self-directed hostility. Problems about revealing their anger were detected among these individuals. Besides, problems in controlling the expression of anger, accompanying impulsive explosive behaviors are also present (4). The current status of obesity treatment is not satisfactory. Some treated individuals regain the lost weight in a short time (5). Many researchers are investigating approaches to keep off the lost weight with treatment strategies to lose weight. In previous reports, it has been demonstrated that most obese individuals returned back to their basal BMIs or to higher values within 1-5 years (6). Nowadays, the question is ‘What is the difference between the ones who keeps off the weight they lose and those who do not?’. Impulsivity is the possible predictor of relapse in obesity treatment (5). Obese subjects are suggested to be more impulsive than lean ones. Impulsive characteristics are higher in obese patients with BED (7). Impulsive people appear to have no control over their behaviors on eating and they have more interest in food with higher calories. Impulsivity is also considered as a predicting factor among patients who quit treatment. In a survey among the children between the ages of 8-12 years in the Netherlands, impulsivity was measured by behavior and the results of treatment were evaluated. As a result, it was demonstrated that impulsive children lose less weight compared to the others. It was also concluded that impulsive children are more prone to eating delicious foods; therefore more attention should be given to their dietary control (5). Another issue supporting the relationship between obesity and impulsivity is the occurrence of obesity in children with attention deficiency and hyperactivity disorder (ADHD) (8). ADHD was detected in most of the children (58%) who were receiving obesity treatment. Also, the BMI of children with ADHD was higher than the control group (9). In addition, there is evidence for decreased levels of D2 receptors in the striatum of obese subjects (10-13). With regard to the therapeutic implications, recent studies indicate that methylphenidate (MPH), a drug widely used for ADHD, reduced overall energy intake with a selective reduction in dietary fat (14,15). Dopamine (DA) exerts neuromodulatory influences over behavior and cognition via the fronto-striato-cerebellar circuitry and pharmacotherapy is thought to target these systems to ameliorate problems with impulsivity, inattention and hyperactivity. To explain the comorbidity of ADHD and obesity, it has been hypothesized that a predisposition to glucose starving and obesity is due to inadequate dopaminergic activity in the reward center of the brain. Consumption of large quantities of carbohydrates (carbohydrate binging) stimulates production and usage of dopamine within the brain and it results in a kind of therapeutic effect (16,17). All this information should guide the planning of treatment. Specific cognitive behavioral approaches developed for the treatment of impulsive behavior could contribute much to the treatment of obesity(18). Key words: Eating disorders, impulsivity, obesity

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S94

Efficacy of psychotherapy in bulimia nervosa

Başak Yücel

Department of Psychiatry, Istanbul University, Istanbul, Turkey E-mail: [email protected], [email protected]

The efficacy and importance of psychotherapy in bulimia nervosa have been examined in many studies recently. Most of the eating disorder experts acknowledge the notion that psychological interventions are the best available treatment for BN. Although different psychotherapeutic recommendations have been offered by NICE (National Institute for Health and Clinical Excellence) and APA (American

S94 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Psychiatric Association), several treatment approaches received strong endorsement for BN. Cognitive behavioral therapy (CBT) is recommended as an effective treatment for bulimic patients and considered the ‘treatment choice’ for BN and binge eating disorder (BED), it is also supported by strong evidence-based literature. With regard to the efficacy of CBT specifically in BN, in various studies CBT was associated with more improvements in bulimic and depressive symptoms of patients than symtoms of control patients in waiting-list and any other psychotherapy cases. In terms of general psychiatric symptoms, studies have not shown any difference between CBT and any other psychotherapy. Other psychotherapy choices have included interpersonal psychotherapy (IPT), dialectical behavior therapy, supportive and psychodynamic psychotherapy, and certain self-help approaches. Thus, in clinical practice there have been a number of evidence-supported treatments for BN patients. IPT is a psychological treatment for BN that has demonstrated long-term outcomes that are comparable to those for CBT. Currently, all controlled studies of IPT for BN have been comparison studies with CBT. Although there have been only few controlled trials of psychodynamic treatment of eating disorders, these reports yielded important findings in this field. Standard dialectical behavior therapy (DBT) has been adapted to address a variety of problematic behaviors associated with emotion dysregulation in bulimia nervosa and also DBT may be used in BN patients with comorbid borderline personality disorder. Beside these, the knowledge in the field of self-help treatments continues to develope. Key words: Bulimia nervosa, psychotherapy

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S94-5

[PS-21] Symposium Title: Treatment approaches to comorbidities of ADHD Treatment approaches to psychiatric comorbidities of ADHD in children

Tümer Türkbay

GATA, Department of Child and Adolescent Psychiatry, Ankara, Turkey E-mail: [email protected];[email protected]

Attention-deficit hyperactivity disorder (ADHD) is highly comorbid with other psychiatric disorders. Each of the comorbid disorders modifies the overall clinical presentation and treatment response. Sometimes there can be more complex situations. For example, depressed children demonstrate diminished concentration and irritability and it may be difficult to differentiate from the cardinal symptoms of ADHD. Children with ADHD and comorbid disorders have poorer prognoses than those with ADHD alone. Both stimulant medications and atomoxetine markedly reduce symptoms of comorbid oppositional defiant disorder, which often requires adjunctive parent training and behavior management. Severely explosive anger may require the use of atypical antipsychotics. In conduct disorder, stimulant medications and atomoxetine also reduce aggressive behavior and antisocial acts. Atypical psychotics or mood stabilizers may be used for highly aggressive-explosive cases. The majority of children with comorbid ADHD/depression can be managed with a psycho stimulant. However, initial treatment with antidepressant drugs should be saved for treating children with more severe depression. Stimulants can exacerbate symptoms of anxiety disorders. Atomoxetine, SSRIs and behavioral therapies reduce anxiety symptoms. If tic disorders are mild or episodic, they usually require no treatment. Most ADHD/tic disorder patients will not demonstrate an exacerbation of their tics with stimulants. Nevertheless, if tics worsen with stimulant use, an antipsychotic or alpha agonist should be added to the psychostimulant. Key words: Attention deficit hyperactivity disorder, comorbidity, management

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S95

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S95 Abstracts of the Invited Speakers

Treatment approaches to psychiatric comorbidities of ADHD in adolescents

Bengi Semerci

Institute, Istanbul, Turkey E-mail: [email protected], [email protected]

Adolescences with ADHD, who suffer from social problems, are under risk of depression, anxiety, destructive conduct disorder, and drug addiction. If there are co-morbid disorders associated with ADHD, it makes the treatment difficult and causes some other complications. The fundamental treatment principles of the psychiatric co-morbidities of ADHD are also effective for adolescence period. However, especially, we should be careful about the conditions that have high prevalence during adolescence period and the conditions which affect prognosis in a negative way. These situations need to be assessed in diagnosis and treatment plan. Anxiety Disorders: Some researches indicate that a stimulant treatment has small effects on anxiety disorder. The treatment of ADHD without anxiety disorder gets more successful results. However, according to recent research, treatment is also effective on anxiety disorder. In general, considering the effect of CBT on the anxiety disorder treatment, it is suggested that CBT beside medication treatment is effective on ADHD having co morbidity with anxiety disorder. If there is co morbidity, it is suggested that the priority needs to be given to ADHD and that if the anxiety symptoms continue, another medication treatment should be considered. Mood Disorders: Depression is an important problem in adolescence period. The important point in treatment is to identify that if ADHD causes to depressive findings or major depression. If ADHD cooccurs with major depression, both of them need to be treated. The treatment may be done either by stimulants or atomoxetine or only by SSRIs or tricyclic anti depressants. The last option is to use the two methods both. When there is co-morbid depression and ADHD, the efficacy of antidepressants is lower than when it is depression alone. In clinical observation, depression findings in adolescence period should be assessed attentively. If there is major depression, the treatment should be carried out together with ADHD. Selective serotonin reuptake inhibitors (SSRI) may be used with stimulants. Conduct Disorders: If ADHD is not treated, it may possibly turn to conduct disorder. In many studies, the use of stimulants for the treatment of co-morbid ADHD and conduct disorder is investigated. The results of these studies show that stimulants are effective when the morbidities are both separate or together. However, if there are co-morbid ADHD and conduct disorder, the effectiveness of stimulants on aggression is lower. If there are co-morbid ADHD and aggression and if the typical ADHD treatment does not work, it may be useful to add atypical antipsychotics to the treatment. If ADHD is co-morbid with conduct disorder, working with adolescents, using behavioural approaches, supporting families and to providing them education about the problem may be helpful. If ADHD co occurs with drug addiction, both disorders should be treated. Stimulants can be used in a controlled way. However, due to addiction, prescribing stimulants may be cause legal problems. Atomoxetine and bupropion could be other options. Eventhough, antidepressants are effective in ADHD, their effectiveness in addiction is limited. Key words: ADHD, adolescence, co-morbidity, treatment

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S96

Treatment of neurological co-morbid disorders in children with ADHD

Murat Yüce

Department of Child and Adolescent Psychiatry, Ondokuz Mayıs University, Samsun, Turkey E-mail: [email protected]

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsive behaviors. ADHD is one of the most common childhood psychiatric disorders. Children with ADHD also have many comorbid disorders and psychiatric symptoms. ADHD may be accompanied with neurological disorders such as epilepsy, headache, and cerebral palsy. Neurological co-morbid conditions can lead to reduction in the level of function, adherence to treatment difficulty, increasing the price of healthcare and medical complications. Therefore, diagnosis and treatment of these neurological co-morbid problems with ADHD are important. ADHD is seen more commonly in children with epilepsy according to the normal population. Approximately 20% of children diagnosed

S96 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers with epilepsy have ADHD as well. Some antiepileptic drugs are known to cause lethargy and impairment of attention. Barbiturates and benzodiazepines may worsen the symptoms of ADHD. It has been reported that some drugs such as tiagabin, zonisamide, and topiramate can cause cognitive slowing and concentration problems. Psychostimulants are frequently used in the treatment of ADHD. It has been reported that these medications do not severely effect epileptic seizures and may improve cognitive functions. In this presentation treatment approaches for children and adolescents with ADHD and co-morbid neurological disorders will be discussed. Key words: ADHD, children, neurological co-morbidity, treatment

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S96-7

Drug interactions of medications for comorbidities of ADHD

Osman Abalı

İstanbul Medical Faculty, Child and Adolescent Psychiatry, İstanbul, Turkey E-mail: [email protected]

ADHD is a very common psychiatric disorder in childhood. Children with ADHD have frequently another psychiatric disorder. Conduct disorder, learning disorder, addiction, and mood disorders are frequently seen in children with ADHD. It has been estimated that 23%- 42% of youth receiving psychiatric drugs are receiving multiple drugs (1). Recently drug interactions have been emphasized in these patients. Stimulant drugs and atomoxetine, which is a non stimulant drug, are used in patients with ADHD. Interactions between these drugs and other psychotropic drugs are important for treatment quality. Drug interactions should be considered to prevent adverse effects and increase treatment quality. Possible drug interactions could impact on liver, intestine, or plasma. There are a lot of important risks due to drug interactions in patients with ADHD. Drug plasma levels can change due to CYP-P450 system interactions. It is estimated that approximately 7% of the population may be poor metabolizers, causing slow metabolism(2). Also inhibitors of the cytochrome P450 can increase drug levels by several folds. Some drugs inhibit these systems very potently so that concentration of drug can reach very high levels. Important complications such as neuroleptic malignnant syndrome, serotonergic syndrome, and hallucinations can be seen during these interactions. Treatment strategies should be reviewed from this perspective. Possible drug interactions couldn’t be exactly predicted by the clinicians for every patient. But potential drug interactions should be considered for every patient. Drug interactions will be discussed at this presentation. The treatment strategies will be updated for long term good quality treatment based on the literature. Key words: ADHD, drug interactions, co-morbidity

References: 1. McIntyre RS, Jerrell JM. Polypharmacy in children and adolescents treated for major depressive disoerder: a claims database study. Journal of clinical psychiatry.2009;70(2):24-46. 2. Barton J: Atomoxetin: a new pharmacotherapeutic approach in the managment of ADHD, Archives of disease in childhood 2005;1(90):26-29.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S97

[PS-22] Symposium Title: How to fight with bipolar disorder? From guidelines to clinical practice: Myths and realities Treatment of mixed episodes of bipolar disorders in manuals. What are the recommendations?

Ahmet Ünal

Gaziantep University, Faculty of Medicine, Department of Psychiatry, Gaziantep, Turkey E-mail: [email protected]

There are still clinical states with uncertainties in psychiatry in terms of diagnosis and treatment. Mixed states in bipolar disorders is one of these states. The Diagnostic and Statistical Manual of Mental Disorders – IV (DSM – IV) defines mixed states as a period in which manic and depressive diagnosis criteria prevail together. However, observing all depressive and manic symptoms together during the mixed

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S97 Abstracts of the Invited Speakers episode is not a common occurrence. The Cincinnati criterion has a more flexible approach in terms of diagnosis; a complete manic states together with at least three depression symptoms is enough to diagnose the case as mixed mania. There are studies that identify mixed mania as “a severe form related to mania,” “a transition period between manic and depressive episodes,” or “a separate emotional state.” 15-20% of all manic episodes have characteristics that belong to the mixed mania. In comparison to a classic manic episode, the mixed mania has a more severe psychopathology. Episodes of dysphoria are observed more frequently, and it is frequently reported that dysphoria is an important part of mixed states. In comparison to a classic manic episode, the duration of hospitalization is longer, the number of attacks is higher, and the good periods are shorter during mixed episode. In addition, the psychotic characteristics and catatonic symptoms are more, and the rate of suicide is higher. The most important element of treating the mixed episode is making the right diagnosis. The basis used to determine the treatment method is the same as those recommended for treating manic episodes. Unfortunately, there are no comprehensive studies that address treating mixed mania. There are limited data related to the efficacy of medications on mixed mania or which medication is better than the other. In general, combining drugs and clinical experiments are required for the short-term and long-term treatment of mixed mania patients. According to the Turkish Psychiatric Association (TPA), the treatment for mixed episodes of bipolar disorder is as follows: The treatment starts with valproate, lithium is added if the decrease in symptoms is not >25% within 4-5 days; in the event that the degree of symptoms do not get better by 50% at the end of three weeks, an alternative is using an atypical antipsychotic and stopping the lithium- valproate combination by gradually reducing the amount given to the patient, or moving on to a lithium – carbamazepine combination, and if >50% progress is not reached at the end of Week 6, it is recommended that patients receive ECT. In comparison to classic manic episodes, the rate of response to mood stabilizers for mixed episodes is lower. Antidepressants should also not be used to treat symptoms of depression during this period. This situation proves the need for other treatment options. Olanzapine can be used effectively in acute and preventative treatment of mixed mania; however, its disadvantages are weight gain, diabetes, and metabolic syndrome risk. Ziprasidone has a high level of effectiveness that incorporated psychotic and mixed mania. There is evidence that risperidone is effective in treating manic episodes; however, the amount of information related to its efficacy in mixed episodes is limited. The number of studies about the efficacy of quetiapine on mixed episodes is also limited. The efficacy of aripiprazole on manic and mixed episodes is addressed by some studies. In conclusion, mixed states in bipolar disorder are common clinical reflections. Mood stabilizer treatment strategies are the form of treatment that gives the best results. Mood stabilizer and antipsychotics can be used in the form of monotherapy or combination. Among these mood stabilizers, valproate is the one that has been studied most and is the most recommended. Aripiprazole, ziprasidone, and olanzapine are the antipsychotics that should be utilized first and foremost. Key words: Bipolar disorder, mixed mania

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S97-8

How are the guidelines prepared? Are they necessary? How to use them? Their benefits and limitations?

Yasin Bez

Dicle University School of Medicine, Department of Psychiatry, Diyarbakir, Turkey E-mail: [email protected]

Some important points when preparing guidelines are search strategies and methods to assess evidence and the criteria for rating the strenght of evidence and making a clinical recommendation. The development of treatment guidelines mostly aims to standardize treatment and to provide clinicians with algorithms, which would be able to carry research findings to everyday clinical practice, by organizing information from diverse sources into an easily accessible format (1). From this point of view, treatment guidelines may be useful to avoid non-evidence-based treatment decisions. Thus, their common use should be supported. On the other hand, they get quickly out- of-date and may interfere with following the most recent treatment approaches. Besides, they may not fully apply to the everyday clinical setting. Besides the benefits and limitations of guidelines another important point is the adherence of the clinicians to these guidelines (1). Despite considerable efforts to develop them, adherence to the treatment guidelines for bipolar disorders are not enough yet. For example a study from United States demostrated adherence of 64.1% of the psychiatrists to the treatment guidelines (2). Another study conducted in France reported a 40% non-adherence rate to treatment guidelines of bipolar disorder among psychiatrists (3). Current and more detailed data about preparation, use, benefits, and limitations of treatment guidelines will be further discussed in this presentation. Key words: Bipolar disorders, guidelines

S98 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

References: 1. Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS. Tretament guidelines for bipolar disorder: A critical review. J Affective Dis 2005; 86: 1-10. 2. Perlis RH. Use of treatment guidelines in clinical decision making in bipolar diorder: a pilot survey of clinicians. Curr Med Res Opin 2007; 23; 467-475. 3. Samalin L, Guillaume S, Auclair C, Llorca PM. J Nerv Ment Dis 2011; 199: 239-243.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S98-9

Maintenance treatment in bipolar disorder: What do guidelines recommend?

Ibrahim Eren

Konya Research and Training Hospital, Psychiatry Department, Konya, Turkey E-mail: [email protected]

Bipolar disorder is a serious mental illness presenting with exacerbations and remissions. Relapses should be minimized and that is achieved by preventive treatments. Developing easily applicable and reachable algorithms by incorporating data coming from various sources, implementing research findings in daily practice, and providing standardized treatment choices are all important. Many guidelines have been published for bipolar disorders so far. American Psychiatric Association (APA) Guidelines: This guidelines recommend preventive treatment after one manic episode. The main goals of treatment are to prevent relapse, resolve subclinical residual symptoms, and to decrease suicide risk. Lithium and valproate are primary agents, as they have the most evidence of efficacy. Their alternatives lamotrigine, carbamezapine, and oxscarbamezapine are secondary agents. In general continuation of preventive medications used during acute management is first choice during maintenance treatment. ECT can be used as a maintenance treatment. Antipsychotics should be discontinued if there is no persistent psychotic symptoms. Cognitive behavioral, interpersonal, and psychodynamic therapies can be used in addition to medications. Psychoeducation is reported to be beneficial. Keeping lithium levels between 0.8-1.0 mEg/L during maintenance phase were mentioned to be more effective. In this guideline generally accepted treatments were mentioned as non-definite recommendations. Texas Medication Algorithm: Acute phase doses should be continued at least 3 months. All patients are recommended to receive antimanic medications during maintenance phase, if necessary some can receive low dose antidepressants. Lifelong maintenance treatment is recomended if patients had 2 manic episodes or one manic episode with positive family history, or the acute episode was very severe. This group of authors think antimanic medications are the core of the treatment and they emphasize depression less. In addition they recommend ECT and tricyclics, which were demonsterated to be effective, in final stages due to side effects and patient preferences. Expert Opinion Series on Medication Treatment in Bipolar Disorder: They recommend continuation of treatment, which was effective in acute phase except in divalproex monotherapy and predominantly depressive cases. They suggest adding lithium in those cases. They recommend that antipsychotics should be stopped during maintenance phase, but some patients may need to continue taking antipsychotics. In that case, one of olanzapine, risperidone, or quetiapine can be chosen. Against manic episode risk they suggest to increase the dose of mood stabilizer, add another mood stabilizer, and try additional treatments afterwards. This algorithm has many structural features and is very detailed. British Psychopharmacology Association Guidelines: According to this guideline lithium is the first choice and second choice medications include valproate, olanzapine, carbamazepine, oxcarbazepine, and lamotrigine. Treatment resistant cases can be treated with medication combinations, clozapine, or ECT. World Federation of Biological Psychiatry Associations Biological Treatments in Bipolar Disorders: It is recommended to use combination of antidepressant and mood stabilizers after depressive episodes. After manic episodes lithium, anticonvulsants, or antipsyhotics are suggested. When first line treatments fail, trying combinations of first line agents is recommended. It seems to be the most balanced guideline published so far. While they avoid newly discovered treatments , they support use of antipsychotics and antidepressants with caution. Canmat: Once the patient becomes asymptomatic, it is suggested to discontinue all medications other than mood stabilizers and to continue maintenance treatment for 6-12 months after a single episode of illness. This guideline has similarities with APA guideline and recommends lifelong maintenance treatment in patients with recurrent episodes or positive family history. Australia and New Zealand Bipolar Disorder Treatment Algorithm: It suggests to avoid antidepressant use during maintenance phase after depressive episodes due to precipitating mania and rapid cycling, but recommends mood stabilizer and antidepressant use in cases with recurrent depressive episodes. The duration of treatment after first manic episode is 6 months and lithium, valproate, carbamazepine,

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S99 Abstracts of the Invited Speakers or lamotrigine are listed as recommended medications to prevent recurrent episodes. NICE Treatment Guidelines: They recommend at least 2 year of maintenance treatment after 1 episode. Long term preventive treatment should be considered in the following cases: One manic episode with prominent risk factors and negative results and bipolar II cases with significant functional loss, suicide risk, and frequent recurrent episodes. Lithium, olanzapine, or valproate can be used in long term maintenance treatment, but valproate should not be used in women with pregnancy potential. When monotherapy with one of those is not adequate, one of three can be added as a second agent or monotherapy can be tried with a different agent. Possible combinations are lithium-valproate, lithium-olanzapine, or valproate-olanzapine. Turkish Psychiatry Association Guidelines: Maintenance treatment is suggested in general after second episode, but it can be started in cases with risk factors. If a mood stabilizer was initiated during acute phase, it should be continued in maintenance phase, if not, then one should be started. When a mood stabilizer will be chosen for maintenance phase, it should be lithium. After second episode, whatever the type of episode was, the same mood stabilizer should be continued if there was one. When there is not adequate response and recurrence occurs a second mood stabilizer should be added. In cases using lithium as first mood stabilizer, valproate should be given priority as the second mood stabilizer. In conclusion, even there are similarities in many areas among guidelines, there are also different recommendations regarding treatment options. Those differences stem from complex clinical presentations of bipolar disorder and different cultural and traditional treatment approaches. Key words: Bipolar disorder, maintenance phase, guidelines

References: 1. Fountoulakis KN, Vieta E, Sanchez-Moreno J, Kaprinis SG, Goikolea JM, Kaprinis GS. Tretament guidelines for bipolar disorder: A critical review. J Affective Dis 2005; 86: 1-10. 2. Perlis RH. Use of treatment guidelines in clinical decision making in bipolar diorder: a pilot survey of clinicians. Curr Med Res Opin 2007; 23; 467-475. 3. Samalin L, Guillaume S, Auclair C, Llorca PM. J Nerv Ment Dis 2011; 199: 239-243.

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S99-100

[PS-23] Symposium Title: Individualized medicine: Focus on pharmacogenetics Genetics and drugs: From research to clinical studies Turkish perspective

Cem Şengül

Pamukkale University, School of Medicine, Department of Psychiatry, Denizli, Turkey E-mail: [email protected]

Genetic studies in psychiatry are on the rise and they form an important portion of all psychiatric research in last years. The genetic studies in psychiatry vary from classical association and linkage studies to genome wide association, and copy number variant studies. Genetic studies were focusing on different dimensions of psychiatric conditions. First of all, associations of target genes with psychiatric disorders were investigated in majority of studies. Association of drugs and genetics were also studied in many research projects. Genetic drug association studies consist of studies with efficacy and frequency of side effects of drug on different genetic polymorphisms. Recently, μ-opiate receptor gene (OPRM1) Asn40Asp single-nucleotide polymorphism was found to be associated with naltrexone drug response in alcoholic patients. This finding was very important for revealing effect of genetics on drug response. Naltrexone was effective in aspartate (Asp) 40 allele carriers but drug was ineffective in homozygote asparagine (Asn) carriers. Different genetic polymorphisms of genes encoding enzymes and receptors that were related to dopaminergic, serotonergic and glutamatergic systems were also associated with antipsychotic and antidepressant drug response and side effects. For example 5-HT2C receptor 759C/T gene polymorphism was associated with antipsychotic induced weight gain and T102C polymorphism of 5HT2A receptor gene was associated with response to risperidone. Genome wide association and copy number variations are new genetic techniques revealing more detailed and reliable results. Studies using these techniques might be more useful for exploring interactions between drugs and genetics. Studies on association of genetics with psychiatric disorders were limited and there were only a few studies available on association of genetics with psychiatric drugs in Turkey. Financial problems and approval speed and requirements of ethics committees are important barriers for conducting studies on genetic drug interaction. Resolving these issues might increase interest of psychiatrists on this topic. Key words: Genetics, polymorphism, drug

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S100

S100 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

Pharmacogenetics and how individualized medicine can be applied to the practice of psychiatry

Çiğdem Aydemir

Ankara Numune Research and Education Hospital, First Psychiatry Clinic, Ankara, Turkey E-mail: [email protected]

Choice of psychotropic agents is a critical problem during the follow up of mentally ill patients. Some of the patients experience remission, however significant proportions of the patients continue to suffer from psychiatric symptoms and side or adverse effects. Psychotropic drug efficiency may not occur until a considerable time after the initiation of the therapy after which the clinician can determine, whether the regimen is effective or not. During this period treated patients may experience continuous psychiatric symptoms, employment loss, social dysfunction, and medical morbidity. Efforts to identify the best possible drug regimen for the patients focused on many points, such as clinical variables, predictors of possible side effects, plasma and CSF neurotransmitter levels, metabolite levels, and brain imaging, but they have only limited success. Up to date in practice, drug selection is made based on clinical symptom profile and possible side effects of treatments. The pharmacogenetics of the psychotropic drugs is a possible way to decide the suitable drug for the patient. Pharmacogenetics is the study of genetically determined interindividual differences in response to pharmalogical agents. In this field there are genetically coded pharmacokinetics (genetically based differences that influence the bioavailability of a drug), pharmacodynamics (genetically based differences in the proteins at which a drug acts) of the drugs, and dynamics of their side effects. The renal clearance of drugs appears to be similar in age- and weight-matched healthy subjects with no defined genetic polymorphisms. Studies regarding the inheritance mostly account for the ability to eliminate drugs. The genetic differences in pharmacokinetics have proved that they may be applied to the most of the drugs metabolism. Genetic polymorphisms have been identified and defined for some drug transporters, primarily P-gp, and several hepatic enzymes important for the cellular transport and metabolism of many drugs used in psychopharmacology. Genetic polymorphism in a drug-metabolizing enzyme can result in subpopulations of people who may deviate from the population mean in their ability to metabolize substrates of the affected enzyme. People who are poor metabolizers constitute at least 1% of the population, but the majority of people are normal or rapid metabolizers, and some are identified as ultra rapid metabolizers. The practical implications of metabolic phenotyping are most meaningful when the metabolic pathways of therapeutically administered drugs are known and when drug concentration has been correlated to either therapeutic or toxic effects. Genetic differences in the receptors, on which the drugs act, are another important factor in predicting the effects and side effects. Findings in this field are scarce in comparison to pharmacokinetics studies however some research projects are in progress. After the results of these studies are obtained; different variables other than plasma concentration of the drug would be available in pharmacotherapy practice. There is a dramatic increase in the amount of availability of the genetic information in public since samples can be easily collected by peripheral blood collection or mucosal smearing. Progress in genetic-molecular technology made possible to conduct genetic research on individual genes or entire genomes. In the future by the help of pharmacogenetic approach clinicians will be able to understand the predictors of drug efficacy and side effects, as a result individualized medicine will be applied in the practice of psychiatry. Key words: Pharmacogenetics, psychiatry, treatment, individualized medicine

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S101

Pharmacogenomics biomarkers and personalized medicine in psychiatry

Yeşim Aydın Son

Middle East Technical University, Informatics Institute Department of Health Informatics, 06800, Ankara, Turkey E-mail: [email protected]

Transformation of clinical medicine was one of the long term goals of the Human Genome Project, expected to impact the practice within 10-20 years after the announcement of first draft of human genome. As of 2011 we are just entering into this era and emerging applications of technologies based on genomic research is indicating that Human Genome Project will be able keep its promise. Translational and clinical research to develop new personalized medicine approaches are going strongly; identification of predictive and diagnostic biomarkers is accelerating with the help of high-throughput technologies, and molecular diagnostics and pharmacogenomics is one of the growing markets worldwide with the goal of early detection, prevention, and intervention of diseases and to predict drug efficacy to guide dosing and avoid adverse reactions.

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Single Nucleotide Polymorphisms (SNPs) are the most common form of genomic variations and the main genetic reason behind individual phenotypic differences. Also SNP variations are suggested to be the underlying reason of many complex diseases, they are considered as a good candidate for personalized medicine and pharmacogenomics applications. Genome-Wide Association Studies (GWAS) of SNPs are among the promising approaches for the identification of disease causing variants. The high-dimension of the SNP genotyping data presents a challenge for the understanding of the genotype and its possible implications for the etiology of the diseases and also for the identification of the representative SNPs to design the follow up studies for the validation of the associations. One of the bioinformatics tools developed to overcome this challenge is METU-SNP (http://metu.edu.tr/~yesim/metu-snp.htm), which aims to fasten the identification of associations described through GWAS. Today through genomic research and meta-analysis of genotyping experiments we are able to reveal SNP biomarkers associated with disease and drug reactions. Next, translational research has to be conducted in order to develop genomic diagnostics to apply this information into practice in medical clinics. Design of diagnostic assays for the diagnosis and prediction of drug response in psychiatric disorders can especially guide the initial selection of antipsychotics or antidepressants based on the individual genomic information of the patients. Development of personalized medicine approaches and utilizing genomic diagnostic assays like the examples will be presented in this talk will eliminate or decrease the number of trial-and-errors in selection of right therapy and dosage for the right patient and will also minimize emergency visits due to side effects of the drugs. Also prescription of right medicine and therapy plan at the initial diagnosis will increase trust between the healthcare professionals and the patients, which in return expected to provide higher cooperation and adherance rates of patients to their therapy. Application of pharmacogenomics and personalized medicine approaches in clinical decision making is expected to decrease the cost of healthcare in psychiatry as in other disciplines, while offering higher quality healthcare.. Key words: Personalized medicine, biomarkers, molecular diagnostics, pharmacogenomics, Single Nucleotide Polymorphisms (SNPs), METU-SNP, rational drug use

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S101-2

[PS-24] Symposium Title: Effects of psychotropics and other drugs on quality of life, employee security, flight and traffic safety The effects of psychotropic and other drugs on flight and flight safety

Muzaffer Çetingüç

Aviation and Space Medicine Center, Anadolu University, Eskisehir, Turkey E-mail: [email protected]

There are data that the side effects of many prescription drugs impair the psychomotor and cognitive performance of patients; with psychotropic drugs having even more of these negative side effects. Particularly drugs like benzodiazepines, antipsychotics, barbiturates, trycyclic antidepressants, stimulants, narcotic analgesics, and that affect the central nervous system top the list for risks of accidents, injuries, and cognitive impairments. Along with these, anticoagulants, chemotherapeutic agents, antidiarrheals, antiemetics, and steroids should not be allowed for pilots. It is debatable that SSRIs have a mild side effect profile. SSRIs and bupropion are given to military pilots up to 6 months after resolution of anxiety and depressive symptoms in Canada and Australia. But the civil aviation authorities did not grant any privileges to these drugs. The gold standard in aviation for a pilot to fly efficiently and safely is to be in good mental and physical health and not to be affected by any medication during flights. The regulations both international and national have clear rules that permanently or temporarily restrain pilots from flying activities in the case of any sickness or medication treatment. The rules stating that a sick person cannot function as a pilot in a plane or an air traffic controller in a tower are rational. However since the notion of being sick and the tasks during a flight spread over a wide range, local health authorities can issue “waivers” for special situations. For example pilots with conditions like type-2 diabetes, asthma, rheumatoid arthritis, sarcoidosis, or melanoma cannot fly; but in certain forms of these conditions that are stabilized with treatment, that have not caused serious limitations, and that do not affect performance, the pilot may be allowed to fly. Atopic dermatitis that recover with application of pomades, allergic rhinitis that is treated with nasal sprays, asthma that is treated with steroid inhalers, type-2 diabetes that is controlled with metformin are examples of allowed conditions. The drugs that are assumed not to have any side effects that might affect flight safety are: Aspirin, paracetamol, most antibiotics, depot penicillins, gout and thyroid medication, antiacids, nasal decongestants, oral contraceptives, topical analgesics and steroids, nonsteroidal anti-inflammatory drugs, vitamins, metformin, modafinil, caffeine, etc. Clearly, the patients need to be monitored for the first few days of use considering these drugs may have idiosyncrasies.

S102 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

It is a problem when pilots take drugs without consulting authorized doctors for fear of flight suspensions. Adding to that reasons like the cost of doctor’s visits, losing compensation for the duration of suspension, upsetting supervisors due to disrupted flight schedules may lead pilots to taking OTC drugs. What’s worse is that they can order DTC drugs over the internet based on unscientific news, articles, and ads. There are several herbal supplements available in the market today that contain suspicious ingredients that claim to treat pain, help flu like symptoms, reduce stress, aid sleep, improve sexual performance, reduce blood fat levels, help lose weight, prevent aging, or provide vitamins and minerals. Therefore the attempts of the pilots to treat themselves create risks and the unknown side effects of those preparations pose serious problems to flight safety. Key words: Psychotropic drugs, SSRI, flight safety, pilots

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S102-3

Sexual side effects of psychotropic and other drugs

Adnan Özçetin

Department of Psychiatry, Duzce University, Duzce, Turkey E-mail: [email protected];[email protected]

Sexual dysfunctions are revealed by different organic and/or psychogenic factors and proceed with the addition of psychogenic reasons to almost all organic reasons. The organic/psychogenic discrimination of etiologies is crucial in sexual dysfunctions. The most important and practical way of discrimination is systematic and detailed history. The diffuse type sexual dysfunction established in elderly people should be considered primarily based on organic reasons. Furthermore alcohol/narcotics, drug abuse, the existence of somatic or systemic diseases also strengthen the possibility of organic based sexual dysfunction. The drugs and ingredients causing significant sexual side effects include: Alcohol and narcotics, antihistaminics, decongestants, diuretics, chemotherapeutics, antiulcer drugs, antihypertensives, anticonvulsants, asthmatic drugs, cardiac drugs, psychotropic drugs (antipsychotics, antidepressants, mood stabilizers, anxiolytics, sedative hypnotics), and others. It is mostly difficult even impossible to learn about the sexual side effects of drugs by physicians. Previous studies have revealed that patients usually didn’t mention the sexual side effects of drugs to their physicians. Therefore the physicians should specifically ask about the sexual side effects of drugs beside the dosage, preferred effects, and other side effects. Besides, relationship between sexual dysfunction and other diagnosis and drugs used by the patient should be considered. There are major unfavorable results of sexual side effects including: Loss of adaptation to drug use, abandonment of drug therapy, deterioration of psychiatric or other diseases, continuation of sexual dysfunctions, and disruption of quality of life. Significant side effects exist during the medical treatment of psychiatric disorders. The mechanism of emergence of sexual dysfunction due to medication use is complicated. Sexual dysfunctions due to medications occur by the effects of medications on peripheral and central neurotransmission. Serotonin mostly reveals negative effects on sexual behavior. However, its effects can also be positive according to receptor subtype and localization. Higher prolactin levels cause sexual dysfunction. The increase in dopaminergic activity has positive effects on sexual desire. Antipsychotics, antidepressants, anxiolytics, and other psychotropic drugs mostly have negative effects on sexual desire and behavior. Psychotropic drugs like bupropion, mirtazapine, moclobemid, reboxetine, and tianeptin have little or no sexual side effects. Even dopaminergic drugs like bupropion have positive effects on sexual desire. Key words: Drug, sexual dysfunction, side effect

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S103

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S103 Abstracts of the Invited Speakers

COURSES

[KC-01] Basic Biostatistics

Selim Kılıç

Gulhane Military Medical School, Department of Epidemiology, Ankara, Turkey E-mail: [email protected], [email protected], [email protected]

The aims of this course are to teach the basic statistical approach and terminology, to teach the use of the SPSS for Windows package program and its basic characteristics and principals, to perform the basic descriptive and analytical statistics by using SPSS for Windows package program and to interpret the results. At the end of the course, the participants will be able to perform descriptive statistics, select the appropriate statistical tests to compare differences between or within groups and be able to draw some graphics by using the SPSS for Windows package program in a datasheet which is composed by the course director. The participants, upon completion of this course, will be able to generate and test hypotheses, compose a datasheet iusing the SPSS for Windows program, enter data in the datasheet, transform the data to other forms, select the appropriate statistical test for comparison of groups and computation of basic statistics, interpret and write the results, interpret the p value and confidence interval, and draw some graphs by using the SPSS program. The participants will learn to calculate mean, median, mode, standard deviation, quartiles, frequency and percents as descriptive statistics. They will learn and differentiate categorical, ordinal, and continuous variables by studying examples. To compare categorical variables, the use of the chi-square test and interpretation of the results will be discussed. For continuous variables, the appropriate test will be determined with respect to group numbers, whether groups are dependent or independent and whether the variables are parametric or nonparametric. According to the existing conditions, the participants will decide when they should use the independent samples t test, ANOVA, paired samples t test, or repeated measures of ANOVA as parametric tests and Mann Whitney U, Kruskal Wallis, Wilcoxon ranked signs test, or Friedman test as a nonparametric tests. They will also use correlation analysis to determine the linear association between continuous and ordinal variables. By using the SPSS program, participants will compose bar and pie graphs for nominal and box plot graphs for continuous variables to demonstrate the results. Key words: descriptive statistics, p value, confidence interval

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S104

[KC-03] CBT in somatization disorders

Axel Würz

Department of Psychiatry, Marmara University, Istanbul, Turkey E-mail: [email protected], [email protected]

Despite a high prevalence of somatic symptoms without demonstrable organic cause in nearly every branch of medicine, understanding, classification and treatment of these disorders have posed a considerable challenge. As the DSM-V is in development, the proposed changes in comparison to the DSM-IV can be seen to reflect the current understanding of non-organic physical symptoms. It is likely that somatization disorder, hypochondriasis, undifferentiated somatoform disorder and pain disorder will be combined into a new category entitled “Complex Somatic Symptom Disorder” (CSSD) which emphasizes the symptoms plus the patients’ abnormal cognitive processes. The term “complex” is intended to indicate that the symptoms must be persistent and must include both somatic symptoms (criterion A) as well as dysfunctional cognitive processes (criterion B) for the diagnosis to be made. Cognitive processes such as dysfunctional attention focusing, symptom catastrophizing, and symptom expectation that may be included in criterion B also show the influence cognitive models have exercised in the understanding of these disorders. These cognitive processes have to be evaluated against the background of possible psychiatric comorbidities, current life stressors, possible past traumatic events and learning experiences that shaped emotion regulation in an unhelpful way. Contributing to the maintenance of symptoms and resulting from dysfunctional cognitions are behaviours such as imbalanced level of activity, avoidance and safety-seeking and reassurance-seeking behaviors.

S104 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org Abstracts of the Invited Speakers

In cognitive behavioural therapy (CBT) of these disorders all the factors maintaining and contributing to the disorder are possible targets for treatment. The first and possibly most important step is to develop, in cooperation with the patient, an alternative explanation of the patient’s symptoms other than the presence of an organic cause. During the course of treatment the patient can then collect evidence that supports the alternative explanation of symptoms. The techniques that can be employed within the framework of the cognitive-behavioral approach are aimed at addressing the underlying dysfunctional cognitive processes and behaviors. They may comprise cognitive restructuring, attention-training, behavioral experiments, exposure, activity planning, and emotional-regulation techniques. Conventionally, treatment can be conducted in individual and group sessions and usually comprises about 15 one-hour sessions. There is evidence showing that CBT is effective in decreasing symptom severity and overall distress. However, there are limited number of studies comparing different treatment modalities such as CBT and pharmacological interventions. Also it is not clear if combining CBT and pharmacological treatment increases effectiveness. In addition different forms of therapy such as computer-based treatment have been developed. The cognitive behavioral model has been influencing the current understanding of somatization and CBT has shown effectiveness in its treatment although further studies are welcomed. Even if a full course of CBT cannot be offered, e.g. in an outpatient setting, and pharmacological treatment is chosen, it appears promising to integrate at least certain parts of cognitive-behavioral treatment such as developing an alternative explanation for the patient’s symptoms and exploring the role of processes such as attention, avoidance, unbalanced activity levels and safety-seeking and reassurance-seeking behaviors. Key words: Somatization, CBT, somatoform, hypochondriasis, treatment

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S104-5

[KC-04] Mindfulness and acceptance based therapies

Kültegin Ögel

Acibadem University, Medical Faculty, Istanbul, Turkey E-mail: [email protected]

Mindfulness has reached far beyond the disciplines where it originated and has become an evidence-based psychotherapy method. In particule, the application of mindfulness based therapies in addition to traditional methods for psychiatric disorders prevents relapses. Mindfulness is concentrating with the aim of focusing at the moment in a nonjudgmental way. Mindfulness means being conscious of the current experience and accepting it. In other words, mindfulness is a unique and receptive form of consciousness in which stimulants are not evaluated, not classified and not analyzed. Mindfulness and acceptance based therapies deal with the thought itself instead of the content of the thought. It may be said that they help cognitive restructuring in this way. Mindfulness and acceptance based therapies differ from cognitive behavioral therapies in that way and are accepted as third wave therapies. Acceptance should not be confused with submission and giving up. Acceptance directs the person to turn to the current experience (opening up) instead of running away from the experience (closing up). By this means, the person learns to be with and accept experiences that are pleasant, unpleasant, or neutral. The person develops the skill of being fair to his or her own experiences. Being aware of what is happenibg causes a willingness to let things that are pleasant or unpleasant happen just as they are. Mindfulness acceptance therapies involves; Mindfulness Based Stress Reduction (MBSR), Mindfulnnes Based Cognitive Therapy (MBCT), Acceptance and Commitment Therapy (ACT), and Dialectical Behavior Therapy (DBT). The common basic strategies that all these therapies use are: - Acceptance - Focusing at the moment - Cognitive defusion and decentering - Being nonjudgmental - Observing Adaptation of the different viewpoints that are offered by mindfulness and acceptance based therapies by therapists, who have understood them, is useful. However, understanding of the basic rationale of the therapy by all psychiatrists and psychologists is also useful. Key words: Mindfulness, acceptance, psychotherapy

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S105

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org S105 Abstracts of the Invited Speakers

[KC-05] Eye movement desensitization and reprocessing method [EMDR] Specifically designed for Turkish patient population in the Netherlands

Serdar Güner

Praktijk Voor Psychiatrie, The Netherlands E-mail: [email protected]

Dr. Serdar Guner reports that those behaviorally troubled Dutch patients with Turkish origin have not necessarily been benefitted by those 10-15 sessions of EMDR during their psychiatric evaluations necessitated by different conditions. The clinicians have reportedly been applying traditional EMDR methods first to be objectifying relaxation through imagination and later on processing the completion of catharsis during as well as after the said eye movements. The patients, however, have been reporting no benefits and even at times, worsened clinical conditions after the given session. Dr. Guner has finally extracted the facts centered on this failure relevant to the given patient population. Those Turkish-Dutch clients have not been acknowledged about the rationale relevant to which-treats-what phenomenon through the catharsis. Lacking of explanation centralized around acknowledgement along with a possible language barrier has been hindering the therapeutic process. This finding has eventually led him to develop a sister method specifically designed for this patient population. He has slowly but steadily, started informing his patients about shock, repression of the feelings during it, and the effect of those repressed emotions on the people in short as well as long term trajectories. He, later on, used metaphors in picturing the process through which the said repressed emotions would be surfaced by means of EMDR. One of the interesting demographics has been the cultural difference of this given patient population. Those Dutch clients with Turkish origins have not been motivated in processing anything if they had not understood what they were doing. While this, in fact, is also true with the people from the other cultures, Dutch-Turks appeared to be a bit more autonomous in directing themselves in comparison with the Western Europeans who have likely been more conformists with their clinicians even when they have not necessarily been understanding what and why they were doing in any recommended method. Dr. Guner reviews his methodology designed for this population during his presentation. Most of the work has been an “acknowledgement” in his following up with his patients. This variant method has been helping PTSD patients’ feeling relaxation even after first two sessions. Dr. Guner reports that about 150 of his patients have been very happy about the outcome of this EMDR variant. Key words: EMDR, PTSD, psychotherapy

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S106

WORKSHOP

[WS-01] Alternative CBT method of panic disorder treatment for Turkish patients

Serdar Güner

Praktijk Voor Psychiatrie, The Netherlands E-mail: [email protected]

I have been working as a psychiatrist and psychotherapist in the Netherlands for more than 20 years during which I have diagnosed and treated many Turkish panic patients by the virtue of sharing the same language, culture, and other demographics of the native land, Turkish Republic. The most important factor that led me to develop a different approach than that of a classical cognitive behavioral therapy -- focusing on neuro-vegetative reactions, neutralizing them through psycho-education and home-work, generating an insight into catastophic thoughts while “living” and finally easing up the panic attacks -- was the given patients’ thinking of the methods as “ridicilous,” and not doing their homeworks or acting as if they completed them even they did not. The alternative method I devised was related to use a lot of metaphors corresponding to the patients’ lives, generating an insight into catastrophic thoughts while “understanding” their bodily dynamics, self-controlling neuro-vegetative reactions, and acknowledging “the mechanism of panic reaction.” Since it is relatively short, not necessitating homework, and easy to understand for the panic stricken patients, it promotes motivation leading to less relapses and even if relapses occur, achieving quicker and easier recovery. The method appears to be effective among the native Dutch patients, as well as immigrants. The presentation will be providing details of this newly applied successful panic treatment. Key words: CBT, panic disorder, psychotherapy

Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S106

S106 Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org