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CNS Drugs 2000 Oct; 14 (4): 289-299 REVIEW ARTICLE 1172-7047/00/0010-0289/$20.00/0 © Adis International Limited. All rights reserved. Depression in Patients with Schizophrenia Prevalence, and Diagnostic and Treatment Considerations Armand Hausmann1 and W. Wolfgang Fleischhacker2 1 Department of General Psychiatry, Innsbruck University Hospital, Innsbruck, Austria 2 Department of Biological Psychiatry, Innsbruck University Hospital, Innsbruck, Austria Contents Abstract . 289 1. The Diagnostic Dilemma . 290 1.1 Is Depression Drug Induced? . 290 2. Clinical Relevance of Depressed Mood in Schizophrenia . 291 3. Prevalence of Depression in Schizophrenia . 291 4. Use of Antidepressants in Schizophrenia . 292 4.1 Efficacy . 292 4.2 Pharmacokinetic Interactions . 293 5. Antipsychotics with ‘Built In’ Antidepressant Properties . 294 6. Conclusions and Recommendations . 295 Abstract Depression is a common comorbid syndrome in patients with schizophrenia. A review of the literature highlights the multitude of different expressions used to describe depression in this context. This fact exemplifies the diagnostic and ther- apeutic inconsistencies found in literature. Former generations of psychiatrists considered that antidepressants could pro- voke psychotic symptoms. Although the evidence is still tentative, it appears to be current common practice for most psychiatrists, having ruled out confounding conditions such as extrapyramidal motor symptoms and negative symptoms, to prescribe antidepressant agents to patients who show depressive symptoms. There are controlled clinical trials that have demonstrated that tricyclic antidepressants are effective in the treatment of depression in patients with schizophrenia. In contrast, the newer antidepressants have yet to be tested in large scale controlled studies. Possible interactions between antipsychotics and antidepressants must be considered when these two classes of agent are prescribed. Monotherapy with novel antipsychotics may be a treatment option, as some such as zotepine, olanzapine and risperidone have shown advantages over traditional antipsychotics in reducing depressive symptoms in patients with schizophrenia. Others have some pharmacological properties that resemble antidepressant drugs. 290 Hausmann & Fleischhacker 1. The Diagnostic Dilemma postpsychotic period. Despite this, postpsychotic depression was included as a diagnosis in the tenth A multitude of different expressions have been edition of the International Classification of Dis- used in the evolutionary course of psychiatry to eases (ICD-10)[7] andappearedintheappendixof describe depressive states in patients with schizo- DSM-IV.[8] In 1981, three research groups reported phrenia. Although increasing knowledge of the na- studies which showed that depressive symptoms ture of depression in schizophrenia has evolved are regular features of schizophrenia, seen most over recent decades, nosological agreement has been frequently in the acute florid phase of the illness difficult to achieve and the different approaches to and gradually becoming less prevalent during re- the diagnosis of negative symptoms and depression mission.[9-12] The term ‘revealed depression’ was are still inconsistent. The constructs used to de- coined.[13] scribe depression in schizophrenia are not well de- fined and their empirical basis appears to be rather 1.1 Is Depression Drug Induced? weak. The list of terms used to describe such de- pression includes: postpsychotic depression, de- There is still inconsistency in the literature con- pressive neurotic response, pharmacogenic symp- cerning the role antipsychotics play in the aetiol- tom shift, pharmacogenic depression, schizoaffective ogy of depression. The background to this discus- disorder, drug-induced depression, post-remissive sion is the fact that antipsychotics antagonise exhaustion syndrome, depressive prodromal state, dopamine receptors. As dopaminergic pathways are akinetic depression, drug-induced dysphoria, re- involved in the reward system,[14-16] antipsychotics vealed depression, and the atypical akinesia syn- are likely to have a negative influence on reward drome. or pleasure and result in anhedonia that may mimic Historically, many of these terms characterise depressive states.[17-21] Helmchen and Hippius[17] the nosological school from which they originated. originally proposed the term ‘syndromegenetic After the descriptive classification by Kraepelin,[1] triad’ (Syndromgenetische Trias) to describe the the concept of depression in schizophrenia became complexity of depressive syndromes seen in pa- largely dominated by psychoanalysis. All psychi- tients receiving antipsychotics. Under this heading, atric symptoms were more or less considered to be they included pharmacologically induced condi- reactions to a harmful psychosocial environment. tions, morbogenic (illness inherent) and individual ‘Depressive neurotic reaction’was the term used at factors. Galdi[22] subsequently coined the term that time. ‘neuroleptogenic’ or ‘pharmacogenic’ depression. Successive redefinitions of schizophrenia start- Most German psychiatrists favoured this concept, ed with Mayer-Gross[2] and continued with Schnei- while most English psychiatrists did not. der[3] and Berner et al.[4] whoexcludeddepression Hirsch et al.[23] stated that depressive symptoms from the core symptomatology of schizophrenia. are less common in severely ill inpatients with Postpsychotic depression was, however, recognis- chronic schizophrenia than would be predicted if ed. The concept of postpsychotic depression encom- these symptoms were manifestations of negative passed the post-remissive exhaustion syndrome,[5] symptoms or drug-induced parkinsonism. Their which assumed that depression may occur as a re- study failed to support the view that long term de- action to being ill, when insight returns after the pot antipsychotic medication plays an important acute psychotic episode. It may be a psychological role in the genesis of depression. This idea was response to the awareness of illness, or a fear of supported by findings from Johnson[9].Inasample relapse. of patients with chronic schizophrenia, depression In 1970, Shanfield and co-workers[6] were the was more common in those patients receiving first to break with the traditional notion that depres- higher doses of depot antipsychotics than in those sive symptoms in schizophrenia are limited to the receiving lower doses.[10] Johnson[10] stated that a Adis International Limited. All rights reserved. CNS Drugs 2000 Oct; 14 (4) Depression in Schizophrenia 291 significant part of depression is not drug related, chronicity, poor social functioning,[35] and sui- but that antipsychotics could play a role in the ae- cide.[36,37] tiology of depression. The onset of depression often signals impend- Barnes et al.[24] founddepressedmoodin13% ing relapse. Herz[38] found that depressive symp- of a group of 194 inpatients with chronic schizo- toms were frequently noticed by patients and their phrenia. Patients were assessed for depression us- families just before rehospitalisation. Similarly, in ing Present State Examination ratings. Those with a 2-year prospective study, Mandel et al.[31] found a rating of 1 (moderate) or 2 (severe) for depressed that relapse occurred in 64% of patients with mood were matched for age, duration of illness and schizophrenia who developed depression com- gender with patients scoring 0 (controls). There pared with 19% of those who were depression-free. were no significant differences in terms of negative Depression also predisposes patients with symptoms, parkinsonism, tardive dyskinesia, anti- schizophrenia to suicide. Suicide in schizophrenia cholinergic medication or current dose of antipsy- occurs at a rate 20 times that of the general popu- chotic drug between the controls and those patients lation; approximately 1 of every 10 patients with with depression. This suggested that depression schizophrenia commits suicide.[39] The majority of was not related to drug treatment, nor was it a direct these patients are depressed at the time of suicide. manifestation or misinterpretation of negative Roy[36] found that over 50% of patients with symptoms. Siris,[25] in a review on depression and schizophrenia who killed themselves had experi- schizophrenia, concluded that it is improbable that enced a past episode of depression and were de- antipsychotics are a cause of depression in patients pressed according to DSM-III[40] criteria at their with schizophrenia, as the data are not conclusive. last episode of contact. These findings were con- However, antipsychotics might be a factor in some firmed by Radomsky et al.[41] individual cases of depression. The possible contribution of drugs to mood dis- 3. Prevalence of Depression orders in schizophrenia is further complicated by the in Schizophrenia existence of a syndrome resembling depressive ill- ness which occurs in association with drug-induced The prevalence of depressive symptoms in parkinsonism.[26] Antipsychotics may generate schizophrenia depends on whether depression is parkinsonian symptoms such as bradykinesia and assessed during the acute or the chronic phase of loss of spontaneity with emotional withdrawal that schizophrenia. Reported prevalence has varied from can mimic depression. The symptoms of this so a low of 7%[42] to a high of 65%.[9,10] Gross and called ‘akinetic depression’, a term coined by Van Huber,[43] in a study in Bonn, Germany, described Putten and May,[26] should respond to anticholin-