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Home , Dysthymia, Major depressive episode, Schizoaffective disorder, Schizophrenia

REVIEW S Afr Rev 2005;8:134-139 Major depressive disorder as a co-morbid diagnosis in versus the diagnosis of – depressed type

Renata Ronelle du Preez, William Charles Griffith, Mark Page Department of Psychiatry, University of Pretoria, Pretoria, South Africa

ABSTRACT The purpose of this article is to focus on the importance of depressive symptoms in patients suffering from schizophrenia, and the dilemma posed by hierarchical classification methods, which exclude co-morbid diagnoses such as Major Depressive Disorder in patients with schizophrenia. The question arises that if Major Depressive Disorder is only categorized under the diagnosis of Schizoaffective Disorder (depressed type), are we able to recognize these symptoms promptly and treat them sufficiently? The duration of the substantial period of depressed referred to in the DSM IV TR criteria for Schizoaffective Disorder is unspecified. We suggest that one should only allocate the latter diagnosis if the substantial period is that of one third or more of the whole duration of the illness. Identification of the optimal cutoff point can generate further hypothesis testing research and refinement of the diagnostic model. It is not only important to refine the diagnosis, but it is even more important to detect these symptoms and treat promptly and effectively. According to the latest literature, the best possible treatment for in schizophrenia appears to be the combination of a second-generation and cognitive .

Keywords: Major depression; Schizophrenia; Schizoaffective; Depressed

Received: 29.11.04 Accepted: 28.12.04

Introduction in considering psychiatric diagnoses. Diagnostic categories At present, psychiatry is in a state of flux and advances in defined by their should be regarded as valid neuroscience and are soon likely to challenge only if they have been shown to be discrete entities with many of its current theoretical underpinnings, particularly natural boundaries that separate them from other disorders. those related to the causation and definition of mental Although most psychiatric diagnostic concepts have not disorders. It is increasingly recognized that the of been shown to be valid in this , many possess high the diagnostic concepts enshrined in contemporary utility by virtue of the information about outcome, treat- classifications of mental disorders cannot be taken for ment response and etiology that they convey and are granted.1 Indeed Goodwin and Guze2 went so far as to therefore invaluable working concepts for the clinician.1 assert that ‘diagnosis is ’ and referred approvingly According to the diagnostic and statistical manual of to P.D.Scott’s observation that the ‘follow up is the great mental disorders (DSM IV TR)3 diagnostic criteria for exposer of truth…..’ It is to the psychiatrist what the post- schizophrenia, major depressive disorder is excluded and mortem is to the physician. should rather be diagnosed under schizoaffective disorder It is important to distinguish between validity and utility (depressed type). Criteria for schizoaffective disorder (depressed type) state that mood symptoms must be Correspondence: present for a substantial portion of the total duration of the Dr RR du Prezz, Department of Psychiatry, University of Pretoria, active and residual periods of the illness, but they do not PBag X113, Pretoria, 0001, South Africa specify the time period.3 It is suggested that this period email: [email protected] must be clearly defined so as to distinguish between

South African Psychiatry Review • November 2005 134 REVIEW S Afr Psychiatry Rev 2005;8:134-139 schizoaffective disorder and the possibility of major Depression may occur in the different phases of the , depressive disorder as co-morbid diagnosis. either during the prodromal phase, psychotic phase or post Previously the diagnosis of schizoaffective disorder was psychotic phase. considered confusing and controversial. The different For the latter we at least have the better definition of classifications (ICD-104 and DSMIV TR3) agree that post psychotic depression in schizophrenia in the research schizoaffective disorder presents a combination of schizo- criteria in the DSM IV TR.3 Kohler16 and Jeczmien17 discuss phrenia-like and affective symptoms, but differ as to the post psychotic depression in schizophrenia in their respec- quality, number and time sequence of the symptoms. tive publications and highlight the significant Hierarchical assumptions at the foundation of the estimated at 25%. Criteria for a diagnostic system stand in the way of recognizing associ- must be met and this episode is superimposed on the ated psychiatric syndromes. It is unclear if associated residual phase of schizophrenia. psychiatric syndromes are separate and distinct co-occur- With regard to depression in the prodromal phases, recent ring or co-morbid syndromes or whether they are part of the research has increasingly focused on the early course of patients’ schizophrenic disorder, i.e. dimensions of schizo- schizophrenia, extending from onset of symptoms to the phrenia that need further attention.5 first treatment contact. A high prevalence of depressive Co-occurring or associated psychiatric syndromes such as symptoms in the early course of schizophrenia has been depression may have been hidden from view by exclusion established in several studies. criteria, which prohibited their being diagnosed in the Hafner et al18 did the so-called ABC schizophrenia study, presence of schizophrenia. a population-based, first –episode study. To study depres- Hierarchical thinking has been present in virtually all sion in the early course of schizophrenia, Hafner’s study systems of psychiatric and has been traced back looked at symptom appearance and accumulation. For this to the tendency in medicine to give each patient only one purpose, four depressive symptoms, without overlap with diagnosis, an approach found in the 17th century. negative symptoms of schizophrenia, namely depressed Bogenschutz6 also emphasized the importance of recogniz- mood, guilt feelings, lack of -confidence and attempted ing multiple diagnoses in one patient to clarify our thinking were used. about categories of illness and the boundaries between Their findings showed that the prodromal phases lasted them as well as the relationship among these categories. on average for 5 years and in total 81% of patients with first With respect to the categorical versus dimensional episode did suffer from depressed mood for at argument one false assumption is that the disorder is either least 2 weeks before admission. On average depressive categorical or dimensional whereas in a real sense every mood emerged as early as 52 months before first admission. disorder is both. It is either present or not, but when the Important for investigating depression in schizo- disorder is present patients may vary with respect to age- phrenia involve the influence of these additional symptoms of-onset, severity, symptomatology, impairment, resistance on the quality of life of these patients, as well as the to treatment and the variety of other disorder characteris- introduction of the second- generation with tics. One of the important issues in using categorical their possible effect is another important approaches pertains to the choice of a cutoff point from .8,109 which the categorical classification is generated.7 The choice for a cutoff point of the duration of depression is The difficulties in diagnosing depression in unclear in schizoaffective disorder and this can lead to schizophrenia erroneous conclusions regarding outcome and stage of Whilst one includes the assessment of hopelessness, illness. suicidality and the degree of depression as central tasks in Identification of an optimal cutoff point must generate a treating affective disorders, this is not always the case for hypothesis, with subsequent research and refinement of patients with schizophrenia. the diagnostic model. Schizophrenic patients present with a myriad of distur- bances in , and communication, and The impact of depression in schizophrenia depression can go unnoticed especially during the acute It is a fact that depression occurs in patients with schizo- phase as noted by Knights and Hirsch.19 They introduced phrenia.8,9,10 The studies on depressive symptoms and signs the term “[un] revealed depression” and argued that these in schizophrenia show a variation from between 7 and 65%, symptoms may be unrecognized because of florid psychotic with a modal rate of 25%.11,12 It is clear that these symptoms symptoms. are of considerable clinical relevance and compromise the It is also the legacy of Kraeplin’s division of psychotic level of functioning of these patients, even to the extent of conditions into affective psychoses and praecox. an increased risk of relapse and suicide.9,10,11 This contributed to the belief that schizophrenia and We all are familiar with the facts that schizophrenia depression were and are distinct and non-overlapping reduces the life span of those afflicted by an average of 10 - entities. Yet again this may influence the threshold for 15 years, and suicide is the leading cause of premature diagnosing important depressive symptoms in patients death among patients with schizophrenia.12,13,14,15 The with schizophrenia. overall lifetime risk for patients with schizophrenia is 50% Distinguishing between negative symptoms and depres- for suicide attempts and they have a 9-13% lifetime risk for sive symptoms can also be difficult in patients with schizo- completed suicide.10,11,12,13 phrenia.

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Numerous studies have investigated the difference assumed that schizophrenia and manic-depressive disor- between depression and negative symptoms. In one study, ders were transmitted by single or at the most two or three an ethologically based comparison done by Schelde20 , the . They commented that the finding of an increased behaviour pattern of schizophrenic patients wasshown to prevalence of the same disorder among close relatives of deviate from the depressed patients in only one specific the original patients strongly indicates that one is dealing behaviour and that is “talking to self”. Their study con- with a valid entity. It seems that the possibility of an firmed the hypothesis that schizophrenic patients have increased prevalence of more than one disorder in the characteristic and specific behaviours, which they called patient’s 1st degree relatives had not occurred to them at endemic behaviours: “nonsocial –talk”, “stereotyped- that time. movements”, “non- stare” and “laughing to self”. Previous studies also showed that schizophrenic patients Schizoaffective disorder or a comorbid diagnosis of demonstrated on a nonverbal ethological scale, more gaze major depression aversion, detached facial expression, looking-down, non- The question, which this article poses, is: when does one specific gaze, less body contact and lack-of-social-smile. decide on a diagnosis of schizoaffective (depressed type) or This as a group in comparison with both a control and when will one include depression rather as a co-morbid depressed group. In the study of Scheld20, it was observed diagnosis on Axis I? that during the first week of hospitalization, the detailed Bermanzohn et al5 proposes that in the case of behavioural manifestations of the depressed patients only schizoaffective disorder the affective part (depressed mood) moderately differed from manifestations seen among the should exist for at least one-third of the duration of schizo- schizophrenic patients and that the significant discriminat- phrenia. ing factor was the “non-social talk.” We suggest the following algorithm to decide if the Specific scales have been developed to rate negative patient is suffering from a schizoaffective disorder (de- symptoms and depressive symptoms independently, pressed type) or a major depressive or namely the Negative Symptom Assessment (NSA) scale and as co-morbid diagnoses. (Figure 1) the Calgary Depression Scale. The NSA was developed to permit the reliable ratings of Figure 1 behaviours commonly associated with negative symp- toms.21 The NSA consists of 16 items with 6 anchors each. The items are prolonged time to respond to questions; the speech quantity; speech content; articulation of speech; emotion range; affect observed for reduced modulation of intensity and reduced display on demand; reduced social drive; poor rapport with interviewer; sexual interest; poor grooming; reduced sense of purpose; reduced interest; reduced daily activity and reduced expressive gestures; slowed movements. The Calgary Depression Scale (CDS) was developed by Addington22 et al in 1990 and is specifically developed to assess depression in schizophrenia. The CDS has 9 items with 4-point severity scale. The items include depression; hopelessness, self-depreciation; guilt feelings; pathological guilt; morning depression; early wakening; suicide and observed depression. in schizophrenia The “schizophrenia spectrum” Several researchers investigated the management of Several disorders have been found to cluster among the depression in schizophrenia and the different options will relatives of patients with schizophrenia, such as major be discussed below. depression, bipolar mood disorders which has given rise to John Cutting24 gives easy approachable guidelines in the concept ‘schizophrenia spectrum’. A number of studies managing a depressive episode. These guidelines include: illustrate this point. For example, three of the putative ensuring that the symptoms are not the of a susceptibility loci associated with (chromo- further psychotic episode, establishing compliance with some 13, 18, 22) seem also to contribute to the risk of prophylactic neuroleptic , (at the correct dosage), schizophrenia.1 Previous studies have supported a provision of psychological support, and if affective symp- genetic contribution to the major categories of psychotic toms persist, adding an antidepressant. disorders and with the Maudsley Twin Psychosis Series study; the estimates for schizophrenia, Augmentation with schizoaffective and were substantial and similar.21 Different opinions exist on adding an antidepressant and on Even earlier studies postulated about the schizophrenia deciding which antidepressant to prescribe. spectrum, such as the study of Robin and Guze’s.23 This Addington et al25 in their international survey of classic paper was written at a time when it was widely psychiatrist’s opinions on the management of depression in

South African Psychiatry Review • November 2005 136 REVIEW S Afr Psychiatry Rev 2005;8:134-139 schizophrenia showed that little agreement exists on the N-oxide increased significantly by 58%, 36% and best management strategy. 38%, respectively. There was no difference in negative It is important to note that adding tricyclic antidepres- symptomatology, as measured by the scale for assessment sant medication to a patient who has psychotic symptoms, of negative symptoms, and the drug combination was may actually retard resolution of positive symptoms.26 In generally well tolerated. The concomitant elevation in contrast, Siris et al8 found was of significant plasma levels of clozapine and its major metabolites benefit for management of depression. suggests that inhibits the metabolism of A few studies showed that adding an antidepressant to clozapine by affecting pathways other than N- their management was not beneficial. Whitehead et al27 demethylation and N-oxidation. Close monitoring of clinical conducted an extensive review of all studies comparing response and, possibly, plasma clozapine levels is recom- antidepressant medication or treatment for patients mended whenever fluoxetine is given to patients stabilized with depression in schizophrenia. The results showed there on clozapine therapy.33 is no convincing evidence to support or refute the use of Taylor et al34 predicted that would not elevate antidepressants in treating depression in schizophrenia. plasma clozapine levels when the two drugs were co- They stated that the literature was overall of poor administered because it does not inhibit the relevant quality, and only a small number of trials made useful enzyme systems. In this preliminary study of five patients contributions. Though their results provide some evidence given citalopram and clozapine there was no overall change to indicate that antidepressants may be beneficial for in mean clozapine levels. Based on this limited evidence, people with depression and schizophrenia, the results, at citalopram might be the antidepressant of choice in patients best, are likely to overestimate the treatment effect, and, at taking clozapine. worst, could merely reflect selective reporting of statisti- Patients in both groups of the study by Kasckow et al35 cally significant results and publication bias. improved on positive and negative symptoms, but the citalopram group had significantly greater improvement in The Selective Reuptake Inhibitors and other HAM-D and Clinical Global Impression Scale scores than the antidepressants control group. There were no major side effects. Serotonin selective reuptake inhibitors (SSRIs) and other Forskolin is a unique activator of adenylate cyclase that anti depressants have been investigated in a few trials. bypasses membrane receptors and directly raised levels of Specifically , citalopram and fluoxetine, the second messenger cyclic AMP. Depressed patients and reboxetine and .28 schizophrenic patients with negative symptoms have been Addington et al28 conducted a randomized, double blind reported to have reduced cyclic AMP levels. In the first prospective placebo controlled study with sertraline on study36 of forskolin in psychiatry, intra venous forskolin was patients with schizophrenia in remission and current major administered in a 75-minute infusion to four depressed and depression. They could not find any significant difference in five schizophrenic patients. All four depressed patients symptoms between the groups. showed a transient mood elevation or stimulation, as did Another study done by Thakore et al29 showed that the two of the five schizophrenic patients. addition of sertraline resulted in global improvement, with a significant reduction in positive and negative symptom Augmentation with mood stabilizers scores and no increase in undesirable neuroleptic side- Mood stabilizers such as and have also effects. Sertraline may act by indirectly reducing dopamin- received attention. Bender et al37 undertook a retrospective ergic activity. Sertraline was found by Kirli et al30 to be more audit of patients on clozapine and lithium and found it was advantageous than imipramine in terms of rapid onset of especially effective with affective symptoms and aggres- action; frequency, severity and duration of side effects, and sion. Basan et al38 conducted a systematic review of ran- relapse risk of schizophrenia. domized trials with valproate as an adjunct to A trial with reboxetine add- on therapy to antipsychotics and found it was beneficial for these pa- failed to demonstrate any significant difference between tients. the placebo and reboxetine groups on any of the outcome Both lithium and valproate have an additional important measures.31 benefit in neurodegenerative . They both Zoccali et al32 conducted a double blind, placebo con- upregulate brain concentrations of cytoreactive proteins, trolled, augmentation study of mirtazapine in patients which exhibit neurotrophic effects, including regeneration treated with clozapine and showed improvement in nega- of CNS .39 tive symptoms. The authors suggested that this combina- tion might act synergistically by increasing in the Antipsychotic medication medial . Another option is that of treating these symptoms with The effect of fluoxetine on the plasma concentrations of optimal antipsychotic medication. Tapp et al40 showed clozapine and its major metabolites was studied in 10 improvement in depressive symptoms after 4 weeks on schizophrenic patients with residual negative symptoms. antipsychotic medication for a sample of patients who were Patients stabilized on clozapine therapy (200-450 mg/day) initially antipsychotic free. Their improvement corre- received additional fluoxetine (20 mg/day) for eight con- sponded with the improvement in both positive and secutive weeks. During fluoxetine administration, mean negative symptoms. plasma concentrations of clozapine, norclozapine and is a second-generation antipsychotic, a

South African Psychiatry Review • November 2005 137 REVIEW S Afr Psychiatry Rev 2005;8:134-139 substituted benzamide. It appears to be an effective agent style present in these groups of patients has been sug- in treating the positive and negative symptoms of schizo- gested as a psychological correlate with depression accord- phrenia. The recommended doses are between 400 mg/day ing to Abramson’s reformulated learned-helplessness and 800 mg/day. Amisulpride demonstrates a good global model.48 This entails the tendency to attribute negative or safety profile, particularly when compared with first- bad events to internal, stable and global causes. Efficacious generation antipsychotics, such as haloperidol. There are short-term group therapy may fill the gap between quality interesting studies that point towards amisulpride's of care and the ideal economic allocation of mental antidepressant effect in speculating on possible care services for people with chronic mental illnesses, for roles in affective psychoses and chronic .41 instance Interactive-Behavioural-Training –a group psycho- Pani and gessa42 imply the proposed mechanism of action therapy model that actively combines cognitive behavioral of substituted benzamides is a selective modulation of the and group process techniques. system in the mesocorticolimbic area. This is important for cognitive processing of internal and external Conclusion cues, related to survival. The selective antagonism of It is the authors’ opinion that depression is a very important dopamine D2-D3 receptors has been evoked to explain, in ‘entity’ in patients with schizophrenia.The aim of this article small to moderate doses (ie 50-100 mg day(-1)), the antide- was to remind and focus clinicians treating patients with pressant effect and, in moderate to medium doses (100-400 schizophrenia on this very important symptom-profile. The mg day(-1)), the reported on negative symptoms of question posed is whether this ‘entity’ should not receive schizophrenia. Thus, substituted benzamides could repre- more recognition and appear as a co-morbid diagnosis in sent the first class of atypical antipsychotics successfully patients with schizophrenia (with depressive symptoms), employed for both depressive states and schizophrenia. fulfilling the criteria for major depressive disorder, provid- Interestingly, recent evidence in the literature suggests that ing these symptoms last for less than one-third of the depressive episodes belonging to the bipolar spectrum are illness. among "alternative indications" of other atypical Early diagnosis and prompt treatment of these symptoms antipsychotics such as and . should improve quality of life. According to current litera- Clozapine is especially linked with studies showing ture it seems that the combination of a second-generation decreased numbers of suicide.43 Olanzapine was shown to antipsychotic and may be the treatment be superior to haloperidol for depression and this effect was of choice. independent of the reduction of psychotic symptoms.44 Olanzapine was also shown to be more effective in the References acute resolution of depression cluster symptoms in com- 1. Kendell R, Jablensky A. Distinguishing between the validity and parison with risperidone.45 utility of psychiatric diagnoses. Am J Psychiatry 2003; 160(1): 4- Risperidone was shown to be more effective than 12. haloperidol for affective symptoms in patients with schizo- 2. Goodwin DW, Guze SB. Preface. In: Psychiatric Diagnosis. New phrenia.46 York: Oxford University Press, 1974: ix-xii. Studies showed no difference between treatment with 3. American Psychiatric Association. Diagnostic and statistical amisulpiride or risperidone as measured by PANSS and the manual of mental disorders: DSM-IV-TR. 4th Edition, text Bech Rafaelsen Scale.47 This study also looked revision: Washington, DC: American Psychiatric Association, at the effect of these antipsychotic on the 2000. quality of life of these patients. Tollefson, Andersen and 4. World Health Organisation. The ICD-10 Classification of Mental Tran45 concluded that concurrent depressive symptoms are Health and Behavioural Disorders. Clinical descriptions and treatment responsive and during treatment with second- diagnostic guidelines. Geneva: World Health Organisation, generation antipsychotics there was an association with 1992. improvement in quality of life. Positive quality of life 5. Bermanzohn PC, Porto L, Arlow PB, Pollack S, Stronger R, Siris advantages were seen with olanzapine and risperdione, but SG, At issue: Hierarchical diagnosis in chronic schizophrenia: a the effects on the PANSS mood item were more robustly clinical study of co-occurring syndromes. Schizophr Bull 2000; influenced by olanzapine. 26(3): 517-525. It is evident that the treatment of depression in schizo- 6. Bogenschutz MP, Nurnberg HG. Theoretical and methodological phrenia is a complicated matter. Evidence does lean to the issues in psychiatric . Harvard Rev Psychiatry 2000; second-generation antipsychotic treatment for the best 8(1): 18-24. responses. The basis for this effectiveness resides in the 7. Kraemer HC, Noda A, O’Hara R. Categorical versus dimensional activity of these agents at multiple approaches to diagnosis: methodological challenges. [Online] receptor sites, including adrenergic, dopaminergic and 2003 [Cited September 2003]. Available from URL: http:// serotonergic receptors. mirecc.stanford.edu. 8. Siris S. Depression in schizophrenia: Perspective in the era of Additional cognitive therapy as treatment modality “atypical” antipsychotic agents: Am J Psychiatry 2000; 157(9): Patients with schizophrenia and depression have similar 1379–1389. cognitive styles to those patients with only depression. 9. Tollefson GD, Sanger TM, Thieme ME. Depressive signs and This supports the potential role for cognitive therapy, symptoms in schizophrenia. Arch Gen Psychiatry 1998; 55: 250- particularly for paranoid patients. The negative attributional 258.

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10. Kilzieh N, Wood AE, Erdman J, Raskind M, Tapp A. Depression imipramine in postpsychotic depressive disorder of in Kraepelinian schizophrenia: Compr Psychiatry 2003; 44(1): 1- schizophrenia. Schizophr Res 1998; 33(1-2):103-11. 6. 31. Schutz G, Berk M. Reboxetine add on therapy to haloperidol in 11. Cohen LJ, Test MA, Brown RL. Suicide and schizophrenia: data the treatment of schizophrenia: a preliminary double-blind from a prospective community treatment study. Am J randomized placebo-controlled study. Int Clin Psychopharmacol Psychiatry 1990; 147(5): 602-607. 2001; 16(5): 275-8. 12. Meltzer HY, Fatemi H. Suicide in schizophrenia: the effect of 32. Zoccali R, Muscatello MR, Cedro C, et al The effect of clozapine. Clin Neuropharmacol 1995; 189(suppl): 18-24. mirtazapine augmentation of clozapine in the treatment of 13. Nyman A, Jonsson H. Patterns of self-destructive behaviour in negative symptoms of schizophrenia: a double blind, placebo- schizophrenia Acta Psychiatr Scand 1986; 73: 252-262. controlled study. Int Clin Psychopharmacol 2004; 19(2): 71-76. 14. Fenton WS. Depression, suicide and suicide prevention in 33. Spina E, Avenoso A, Facciola G, Fabrazzo M, Monteleone P, Maj schizophrenia. Suicide Life Threat Behav 2000; 30(1):34-49. M, et al. Effect of fluoxetine on the plasma concentrations of 15. Harris EC, Barraclough B. Suicide as an outcome for mental clozapine and its major metabolites in patients with disorders; a meta-analysis. Br J Psychiatry 1997; 170: 205-228. schizophrenia. Int Clin Psychopharmacol 1998; 13(3):141-145. 16. Kohler CG, Lallart EA. Postpsychotic depression in 34. Taylor D, Ellison Z, Ementon Shaw L, Wickham H, Murray R. schizophrenia patients. Curr Psychiatry Rep 2002; 4(4): 273-8. Co-administration of citalopram and clozapine: effect on plasma 17. Jeczmien P, Levkovitz Y, Weizman A, Carmel Z. Postpsychotic clozapine levels. Int Clin Psychopharmacol 1998; 13(1):19-21. depression in schizophrenia. Isr Med Assoc J 2001; 3(8): 589 –92. 35. Kasckow JW, Mohamed S, Thallasinos A, Carroll B, Zisook S, 18. Häfner H, Löffler W, Maurer K, Hambrecht M, An der Heiden W., Jeste DV. Citalopram augmentation of antipsychotic treatment Depression, negative symptoms, social stagnation and social in older schizophrenia patients.Int J Geriatr Psychiatry 2001; decline in the early course of schizophrenia. Acta Psychiatr 16(12):1163-1167. Scand 1999; 100: 105-118. 36. Bersudsky Y, Kotler M, Shifrin M, Belmaker RH.A preliminary 19. Knights A, Hirsch SR. ‘Revealed depression’ and drug treatment study of possible psychoactive effects of intravenous forskolin in for schizophrenia. Arch Gen Psychiatry 1981; 38: 806-811. depressed and schizophrenic patients. Short communication. J 20. Schelde JT. Schizophrenic, depressed and nonpsychiatric Neural Transm 1996; 103(12): 1463-1467. medical patients: an ethologically based comparison. J Nerv 37. Bender S, Linka T, Wolstein J, et al. Safety and efficacy of Ment Dis. 2000; 188(6):377-380. combined clozapine-lithium pharmacotherapy. Int J 21. Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester Neuropsychopharmacol 2004; 7(1): 59-63. TR, Davies NJ, et al. Heritability estimates for psychotic 38. Basan A, Kissling W, Leucht S. Valproate as an adjunct to disorders: the Maudsley twin psychosis series. Arch Gen antipsychotics for schizophrenia: a systematic review of Psychiatry 1999; 56(2): 162-168. randomized trials. Schizophr Res 2004; 70(1) 33-37. 22. Addington D, Addinton J, Schissel B. A depressed scale for 39. Vajda FJE. Valproate and neuroprotection. J Clin Neurosc 2002; schizophrenics. Schizophr Res 1990; 3: 247-251. 9(5): 508-514. 23. Robins E, Guze SB. Establishment of diagnostic validity in 40. Tapp A, Kilzieh N, Wood AE, Raskind M, Tandon R. Depression psychiatric illness: its application to schizophrenia. Am J in patients with schizophrenia during an acute psychotic Psychiatry 1970; 126:983-987. episode. Compr Psychiatry 2001; 42 (4): 314-8. 24. Cutting J, Affective symptoms and schizophrenia: what are the 41. Green B. Focus on amisulpride. Curr Med Res Opin 2002; implications for diagnosis and treatment? In: Hawton K, Cowen 18(3):113-117. P eds. Practical problems in clinical psychiatry. New York, 42. Pani L, Gessa GL. The substituted benzamides and their clinical Oxford Medical Publications, 1992: 173-183. potential on dysthymia and on the negative symptoms of 25. Addington DD, Azorin JM, Falloon IR, Gerlach J, Hirsch SR, Siris schizophrenia.Mol Psychiatry 2002; 7(3):247-253. SG. Clinical issues related to depression in schizophrenia: an 43. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for international survey of psychiatrists. Acta Psychiatr Scand 2002; suicidality in schizophrenia: International Suicide Prevention 105(3): 189-95. Trial (InterSePT). Arch Gen Psych Jan 2003; 60(1): 82-91. 26. Kramer MS, Vogel WH, DiJohnson C, Dewey DA, Sheves P, 44. Tollefson GD, Sanger TM, Lu Y. Depressive Cavicchia S, et al. Antidepressants in depressed schizophrenic in schizophrenia: a prospective blinded trial of olanzapine and inpatients, a controlled trial Arch Gen Psychiatry 1989; 46: 922- haloperidol. Arch Gen Psychiatry 1998; 55: 250-258. 928. 45. Tollefson GD, Andersen SW, Tran PV. The course of depressive 27. Whitehead C, Moss S, Cardno A, Lewis G. Antidepressants for symptoms in predicting relapses in schizophrenia: a double people with both schizophrenia and depression. Cochrane blind, randomized comparison of olanzapine and risperidone. Database Syst Rev 2002; (2): CD 002305. 1999; 46(3):365-373.. 28. Addington D, Addington J, Patten S, Remington G, Moamai J, 46. Peuskens J, Van Baelen B, De Smedt C, Lemmens P. Effects of et al. Double-blind, placebo-controlled comparison of the risperidone on affective symptoms in patients with efficacy of sertraline as treatment for a major depressive episode schizophrenia. Int Clin Psychopharmacol 2000; 15:343-350. in patients with remitted schizophrenia. J Clin 47. Keck PE, Strakowski, SM, Mc Elroy SL. The efficacy of atypical Psychopharmacol 2002; 22(1): 20-25. antipsychotics in the treatment of depressive symptoms, 29. Thakore JH, Berti C, Dinan TG. An open trial of adjunctive hostility, and suicidality in patients with schizophrenia. J Clin sertraline in the treatment of chronic schizophrenia. Acta Psychiatry 2000; 61(suppl): 4-9. Psychiatr Scand 1996; 94(3):194-197. 48. Addington D, Addington J, Robinson G. Attributional style and 30. Kirli S, Caliskan M. A comparative study of sertraline versus depression in schizophrenia. Can J Psychiatry 1999; 44: 697-700.

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