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Psychiatria Danubina, 2011; Vol. 23, No. 2, pp 152–156 View point article © Medicinska naklada - Zagreb, Croatia

PSYCHIATRIC ASPECTS OF DISEASES Mirela Vlastelica Private psychiatric practice, Medical University School, University of Split, Split, Croatia

received: 30.5.2010; revised: 15.3.2011; accepted: 22.5.2011

SUMMARY This review clarifies the fact that basal ganglia diseases are psychiatric as much as neurological diseases. It illustrates psychiatric aspects in Parkinson's disease and other hereditary basal ganglia diseases such as Wilson's disease, Huntington's and others. In these diseases, psychological disorders can be difficult to diagnose, whether they are concomitant with the primary (neurological) disease, they are its consequence, or they are the result of a specific pharmacotherapy prescribed for these disease, etc. Thus, the choice of appropriate psychopharmacotherapy for these disorders represents a very subtle problem.

Key words: basal ganglia - psychiatric aspects - comorbidity

* * * * * INTRODUCTION Diagnosing is not easy since clinical symptoms of depression often overlap with the symptoms of PD (e.g. Basal ganglia diseases, like many other neurological unmodified affect, work disability, lack of drive, loss of diseases, manifest different psychiatric disorders as libido, etc.). However, depression in PD is qualitatively clinical features. It is therefore justified to consider different from primary depression in that the sense of them neuropsychiatric and not only neurological guilt, self-destructive thoughts and suicide are much less disorders. Psychiatric issues can be an integral part of frequent (Allain et al. 2000). neurological disease, but they may also occur in the However, there are three major issues related to comorbidity. treatment of depression in PD: Having been recognized to have a leading role in the 1. Do antidepressants induce parkinsonian symptoms? control of motor functions, basal ganglia also have a Tricyclic antidepressants can improve motor role in integration of with cognitive and motor symptoms of PD ( effect), while SSRIs behavior. are mentioned as antidepressants that can induce Thus, psychiatric symptoms should not be observed parkinsonian symptoms ( effect). There is as secondary or additional phenomena in these not enough data yet about (serotonin and disorders. noradrenalin reuptake inhibitor, dual effect), for Psychological disorders in basal ganglia diseases can instance. be difficult to diagnose, whether they are concomitant 2. The safety of antidepressants is questionable in with a neurological disease, they are its consequence, or PD – tricyclic antidepressants can cause delusions, they are the result of a specific pharmacotherapy cognitive disturbances, or orthostatic hypotension prescribed for the primary (neurological) disease. (while blocking alpha-adrenergic receptors), and in this On the other hand, patients can be as sensitive to sense, SSRIs are safer. side effects of the medication prescribed for the primary 3. What are the interactions between antidepressants disease as to the associated psychopharmaceutical, and antiparkinsonian medications? which further complicates clinical features. SSRIs are known for their ability to cause serotoner- Therefore, the choice of appropriate psycho- gic (changes in mental status, delusions, pharmacotherapy for these disorders represents a very , prespiration, hyperreflexia, , diar- subtle problem. rhea, fever; this syndrome can even be fatal). However, This paper presents psychiatric aspects of it is also known that SSRIs are safer than tricyclic Parkinson's disease and aspects of hereditary basal antidepressants when cardiovascular side effects are ganglia diseases such as Wilson disease, Huntington's concerned. On the other hand, antiparkinsonian drugs chorea and other diseases. themselves can cause important changes in mental status so that the interaction between antidepressants and antiparkinsonian drugs is always a topical issue. DEPRESSION IN PARKINSON'S DISEASE (PD) Other researches on depression in PD, for instance the one of Slaughter and associates (http://neuro. Psychiatric symptoms often coexist with Parkinson's psychiatryonline.org/cgi/content) who studied MEDLI- disease, while depression and anxiety are the most NE, focused their analysis on 45 case studies of PD common conditions accompanying this disease. depression covering the period from 1922 to 1998. The

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research showed that the prevalence of depression was Nevertheless, panic attacks are rarely described in 31%, while clinical manifestations included: , the context of the newly discovered PD. While it is safe psychomotor retardation, disfunction, pessi- to assume that PD medications can cause hallucinations, mism, irrationality, and suicidal thoughts and behavior. those patients who do not take the medication can also Depression was treated with SSRIs, most commonly be susceptible to hallucinations and are therefore with . representative of de novo PD (Matsui et al. 2006). From Again, some other studies mention a 40-50% this we can conclude that the pathogenesis of panic prevalence of depression in PD; they also discuss the attacks in PD is practically unknown. It probably has to efficiency of antidepressants in PD depression treat- do with the noradrenergic system. ment. Even though case studies indicate that SSRIs may Furthermore, since degeneration of the raphe is potentially worsen motor symptoms of PD, they are still considered a disorder of the serotonergic system, the chosen as the first choice medication for treatment of serotonergic system plays a role in PD as well. PD depression. Still, the source of greater distress for both the Hoogendijk and associates (http://neuro. patients and those who look after them is the occurrence psychiatryonline.org/cgi/content) have established that of in PD. Although the availability of atypical the prevalence of the depression concomitant with PD to some extent solves the clinical varies greatly in literature. This can be explained by dilemma of how to preserve motor functions while psychosis is treated, our understanding of psychosis in certain symptoms that overlap, so that the newly PD is still in its infancy. established category in DSM-IV „mood disorder due to a general medical condition“ is justified. Depression, panic attacks and psychosis can be predecessors as well as part of PD. However, the

clearest cases are those caused by antiparkinsonian OTHER PSYCHIATRIC DISORDERS drugs. IN PARKINSON’S DISEASE Two thirds of patients with PD experience mood swings and fluctuation of motor functions. Many Parkinson disease is often followed by both researchers indicate that mood swings are related to emotional and cognitive disorders. As already said, motor fluctuation in that patients experience decline in depression is frequent, then anxiety, phobia and apathy. their mood during immobility („off“), and improvement Hallucinations, delusions, sleep disorders, etc. are also when they are „on“ (mobile). However, motor and possible. emotional conditions are not in consistent correlation. In psychiatric practice there are frequent examples When they are correlated, the most common pattern is that increasingly point to the existence of psychological common occurrence of poor mood, increased level of disturbances, most commonly depression that can be an anxiety, and reduced motor functions (http://neuro. integral part of Parkinson's disease. Very often depres- psychiatryonline.org/cgi/content). sion is the early symptom because of which a patient is Maia et al. (http://neuro.psychiatryonline.org/cgi/ brought to his doctor, most commonly a psychiatrist, content) have evaluated the frequency of OCD and only after a thorough observation is performed is an (obsessive-compulsive disorder), OCS (symptoms), and early stage of Parkinson's disease diagnosed. related conditions – such as , , and Likewise, there are many examples of older patients body dysmorphic disorder in 100 patients with PD and who develop an emergency due to sudden attacks of 100 control respondents. In comparison to the control choking, dyspnea, and tachycardia. After a cardiac group, OCD, OCS and related disorders have not been observation is made, cardiac etiology of disorders is more frequent in PD. Nevertheless, studies have ruled out and most commonly a panic attack is diagno- detected the correlation between some OCSs and the sed. However, resting tremor of the hands, slowness of left-sided predominance of motor symptoms in PD. This movement, or rigidity of the limbs etc. is subsequently suggests that the expression of obsessive compulsive identified. In these cases SSRIs may reduce symptoms, symptoms can be referred to right side hemisphere but can not eliminate them. Only after L-dopa therapy is activity. applied, will neurological symptoms improve and panic attacks are reduced as well. AND However, there are psychiatric and cognitive side PARKINSON'S DISEASE effects that are induced by antidepressants themselves (Starkstein & Merello 2007), which certainly has to be According to studies available at http://neuro. taken into account. Panic attacks in PD can also be a psychiatryonline.org/cgi/content, patients with dystonia long term complication resulting from L-dopa therapy. show a prevalence of the following: major depressive This is because a decrease of dopaminergic activity of disorder 25%, bipolar disorder 7.1%, atypical bipolar the striatal receptors can induce disinhibition in locus disorder 7.1%, social phobia 17.9% and generalized ceruleans, hence the increase of the central noradre- (GAD) 25%. This is significant in nergic activity can hypothetically cause a panic attack. comparison to the control group (p<0.005). Of these,

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social phobia and GAD preceded dystonia, while body (www.medscape.com/viewarticle). The bipolar disorder developed secondarily, after the prevalence of PD, the most common basal ganglia appearance of dystonia. disease, is approximately 1 per thousand, and in persons In these studies, simple phobia was significantly of 65 years of age up to 1%. important with PD patients (35.7%, p<0.0001), as much Visual hallucinations in PD are correlated with as atypical depression (21.4%). Additionally, PD was (visual) agnosia, memory disorder, disorder in reality associated with primary phobia and secondary atypical testing, and REM sleep behavior disorder. depression. Basal ganglia have been recognized as having a These results are considered in light of the leading role in the control of motor functions as well as pallidothalamic physiology in dystonia and in PD. in integration of with cognitive and motor behavior. PROGRESSIVE SUPRANUCLEAR Therefore, psychiatric symptoms should be observed PARALYSIS AND PARKINSON'S as secondary or additional phenomena linked with these disorders. DISEASE

Patients with progressive supranuclear paralysis HEREDITARY BASAL (PSP) show significantly more apathy and disinhibition, GANGLIA DISEASES while patients with PD show more hallucinations, delusions and depression. Hereditary diseases of basal ganglia such as Studies show that patients with PSP have symptoms Huntington's disease, Wilson's disease and Fahr's compatible with a lesion of the orbitofrontal and medial disease rarely present with an initial psychotic frontal cortex, such as disinhibition and apathy. On the syndrome, which is hard to differentiate from the other hand, PD patients show symptoms related to prodrome of (www.medscape.com/ monoaminergic disorder, such as psychosis and viewarticle). depression. HUNTINGTON'S DISEASE (autosomal dominant disease) is typically followed by chorea and progressive BASAL GANGLIA CALCIFICATION dementia. Affective psychiatric symptoms and psycho- sis are very common. Psychosis may be the first sign of the disease, especially if the disease appeared early. In the study of Edward Lauterbacha et al. (1994) two cases of basal ganglia calcification including globus WILSON’S DISEASE (lenticular degeneration) pallidus are shown. Both patients had cognitive dys- damages liver and in general, and very rarely functions, symptoms similar to temporal lobe syndrome appears in the form of isolated psychosis. Wilson's (, perceptual disfunction, and visual hallucina- disease is the most significant of these three diseases tions in particular) and myoclonus. The first patient because it can be effectively treated. The pathognomic manifested depression, auditory hallucinations, anxiety, Kayser-Fleischer's ring (which may not always be paranoia and postural tremor. The second patient present), low serum ceruloplasmin levels and high manifested multifocal dystonia with dystonic tremor. 24hour urine copper levels are sufficient for diagnosing the disease. Liver biopsy with the quantitative These cases complement reports on psychotic measurement of copper is the gold standard for definite phenomena and dementia related to the pathology of the diagnosis. Genetic testing is impractical as there are pallidum. They open a new pathophysiological insight over 100 identified mutations and symptomatic and into the possible role of the in asymptomatic mix of heterozygotes. neuropsychiatric conditions. The cases point at a specific pattern of hallucination, paranoia, depression, FAHR'S DISEASE (familial idiopathic basal myoclonus and dystonia. This can further indicate its ganglia calcification) remains controversial with regard role in the genesis of schizophrenia, mood disorders, to psychiatric symptoms and psychosis. Basal ganglia and anxiety disorder. calcifications are typically detected on CT scans by accident because they also exist in families with

asymptomatic heritage. On the other hand, the HEREDITARY BASAL correlation between psychosis and idiopathic basal GANGLIA DISEASES AND ganglia calcification is evident in certain families. GERIATRIC PSYCHIATRY Huntington’s disease in particular can be considered a paradigm of neuropsychiatric disease as it has all three Basal ganglia diseases are common in older people. components, „Triad syndrome 3D“: , Even though motor disorders are the leading symptoms, dementia, depression (http://psy.psychiatryonline.org/ neuropsychiatric symptoms are common and have cgi/content). significant clinical consequences. Studies show that Degenerative diseases such as Huntington's, dementia appears with the majority of PD patients and it Parkinson's and Wilson's disease are traditionally is difficult to differentiate this dementia from Lewy- classified as movement disorders. However, cognitive

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and psychiatric manifestations are equally important. better tolerated, as well as more recent antidepressants This group of diseases also include progressive such as venlafaxine. supranuclear paralysis (PSP), idiopathic basal ganglia If depression is followed by delusions, halluci- calcification, familial calcification of basal ganglia (or nations, and significant agitation, (anxiety) it is Fahr’s disease), neuroakanthocytosis, Sydenham's necessary to include antipsychotics in the treatment. If chorea and postencephalitic . there is no choice, one should know that depressive In his original description of the disease that bears patients with HD usually tolerate ECT perfectly well. his name (HD), George Huntington established that The treatment of the primary disease may be sufficient there exists “a tendency to insanity and suicide“. It has if depression is a secondary occurrence in a disease (e.g. been found that in HD the prevalence of lifelong mood hypothyroidism). So, in Wilson’s disease treatment with disorder is 38%, while 22% of patients meet the major penicillin is often used and it improves the psychiatric unipolar depression criteria. The suicide rate in HD is 4- as well as the neurologic symptoms. 6 higher than in general population, and especially Even though depression in HD is the most common so with people older than 50. psychiatric disease, a small number of patients may The neuropathological basis of depression in HD become manic with euphoric or irritable mood; may get could be related to early neuronal lesions in the impulsive and hyperactive; they may get sleeplessness caudatum medialis, which is correlated with limbic and delusions of grandiosity. Some may even have a structures. Subcortical structures that are damaged in classic bipolar disorder. Mania and hypomania in HD basal ganglia diseases, such as the caudatum in HD, are patients occur with prevalence of 4-10%. They need to connected with the orbitofrontal and be treated with mood stabilizers. However, in cases of by complex frontal-sub cortical pathways. PET shows it should not be lithium, as patients reduced metabolism of the prefrontal cortex in depres- react to lithium less and are more susceptible to sive patients without primary neurological disease. intoxication. Antipsychotics and ECT may also be In Wilson's disease (lenticular degeneration) the included in the treatment. prevalence of depression is 20%. Depression may also occur in progressive supranuclear paralysis (PSP), the PSYCHOSIS AND BASAL disease that degenerates basal ganglia, medulla GANGLIA DISEASES oblongata and . Personality changes and A hypothetical correlation between basal ganglia labile affects occur side by side with the depression. pathology and primary psychotic disorder has been Usually, depression is underdiagnosed in patients established. For instance, many of the Parkinson’s with a basal ganglia disease. Communication with disease (PD) symptoms including poverty of speech, flat patients may be damaged; irritability, agitation or social affect, and psychomotor retardation constitute the withdrawal may also occur. Furthermore, because of negative symptoms of schizophrenia. Likewise, it is such a situation, patients may get demoralized, loose known that schizophrenic patients who are on self-confidence and crave for death. Nevertheless, an antipsychotics can develop extra pyramidal syndrome opinion that depression in these circumstances (these like PD. diseases) is “understandable”, sometimes misleads doc- Recent studies show a greater frequency of tors to accept the reactive origin of patient’s symptoms psychosis in patients with Huntington’s disease (HD), prematurely, thus failing to apply an appropriate and between 3-12%. There is also a higher risk of psychosis more aggressive treatment. In deciding between in earlier stages of HD. “reactive” and “organic” etiology of depression, a The neuropathology of psychosis in HD has not clinician must examine previous history of depressive been understood yet. It is possible that a relative hyper episodes, presence of depression among relatives, dopaminergic condition, which results in selective specific losses in his/her life, life changes, everything degeneration of that contain other that preceded the episode. (so that is relatively Also, there is a risk of diagnosing wrongly higher), influences subcortical pathways leading to (overdiagnosed). Physical changes such as weight loss, psychotic symptoms. In psychosis with HD, PET shows sleeping disorder, bradykinesia, weaker facial a drop of metabolism in the anterior of both expression, apathy etc. can be mistaken for a major hemispheres, which is similar to the relative hypo depressive episode, which may lead to unnecessary frontality seen in PET of schizophrenic patients. pharmacotherapy of the patient who is particularly In Wilson’s disease, psychosis is rarer; it occurs in sensitive to CNS side effects of antidepressants. less than 2% cases. As long as there is no antidepressant that will be Postencephalitic parkinsonism (microscopic focal uniquely effective in these diseases, patients suffering of and basal ganglia) can from basal ganglia diseases are particularly sensitive to also manifest in the form of psychosis. The harmful side effects such as sedation and anticholinergic manifestation is more of a delirium than a psychotic causes of cognitive disorders. Therefore, tricyclics are condition. Chronic sequelae cause personality disorder not considered first choice medicine, but SSRIs are and a full scale of symptoms similar to schizophrenia.

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According to some studies (Davison and Bagely, 2007), be observed as secondary or additional phenomena in 15%-30% of these patients have paranoid-hallucinatory these disorders. Basal ganglia disorders are neuro- psychosis, and 10 % of them have a condition similar to psychiatric disorders indeed, not simply a neurological the once described “dementia praecox“ (http://psy. condition. psychiatryonline.org/cgi/content). Psychological disorders affecting the basal ganglia Finally, Fahr’s disease (or familial idiopathic basal can be difficult to diagnose, whether they are con- ganglia calcification), a disorder characterized by comitant with the neurological disease, they part of a parkinsonism or , , comorbidity or its consequence. They can often be the focal cortical deficit such as dysphasia, can be result of a specific pharmacotherapy prescribed to these manifested in psychosis. patients. A new episode of psychotic symptoms, even with Patients can be sensitive to the side effects of patients with basal ganglia disease, requires a search for medication, be it the medication prescribed for the precipitating factors. They can often be induced by primary disease or a psychopharmacological medica- antiparkinsonian medication, because a hyper- tion. This may create difficulties when selecting an dopaminergic condition or anticholinergic delirium adequate psycho-pharmacotherapy in patients suffering occurs at that point. from basal ganglia disease. The use of antipsychotics in basal ganglia diseases is complex because of the risk of deterioration of the REFERENCES primal disease (basal ganglia). To that effect it is better to avoid higher doses of high potent antipsychotics 1. Allain H, Schuck S & Mauduit N: Depression in (classic) and switch to atypical antipsychotics Parkinson's disease. BMJ 2000; 320:1287-1288. (olanzapine, risperidone, ) as they are better 2. Lauterbach EC, Spears TE, Prewett MJ, Price ST, Jackson tolerated. should be paid to the development JG, & Kirsch AD: Neuropsychiatric disorders, myoclonus, of caused by medication, because it and dystonia in classification of basal ganglia pathways. may then be considered a prime disorder. Biol Psychiatry 1994; 35:345-351. 3. Matsui H. et al. Parkinson's disease following panic disorder. J Neuropsychiatry Clin Neurosci 2006; 18:130- CONCLUSION 133. 4. Starkstein SE & Merello: Adobe eBook Reader (ISBN-13: Basal ganglia, recognized to have the leading role in 9780511033872) the control of motor functions, also have a role in 5. http://neuro.psychiatryonline.org/cgi/content integration of emotions with cognitive and motor 6. http://psy.psychiatryonline.org/cgi/content behavior. Therefore, psychiatric symptoms should not 7. www.medscape.com/viewarticle

Correspondence: PhD. Mirela Vlastelica, Ass.Professor Vukasovićeva 10, 21000 Split, Croatia E-mail: [email protected]

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