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Depression in Schizophrenia: Perspective in the Era of “Atypical” Antipsychotic Agents
Samuel G. Siris, M.D.
Objective: The author sought to provide a contemporary understanding of depression in schizophrenia and promote a treatment orientation. Method: Computer and library-based resources were used to review the literature on depression in schizophrenia. Results: Despite multiple definitions of “depression,” a substantial rate of depression has consistently been found in patients with schizophrenia. A differential diagnosis can be used to advance the understanding and treatment of depression in schizophrenia, and changes in response to the advent of atypical antipsychotic agents can be understood in the context of this differential diagnosis paradigm. Conclusions: Depression is an important co-occurring syndrome in schizophrenia. In at least some schizophrenic patients, the stress-vulnerability model has potential as an integrating concept concerning the relationship between depression and psychosis.
(Am J Psychiatry 2000; 157:1379–1389)
lthough schizophrenia and depression have historically been considered to be separate diagnostic disorders, the observation has repeatedly been made that, from a symptom perspective, depression-like phenomenology occurs quite frequently in schizophrenia (1–4). In the early decades of psychopharmacology, however, it seemed most important to differentiate schizophrenia and depression in order to define most clearly which patients should be treated with antipsychotic agents and which with antidepressants. Nevertheless, the occurrence of the phenomenology of depression in a substantial percentage of patients with schizophrenia (as well as psychosis in patients with depression) has kept alive the twin issues of the appropriate descriptive boundaries between the two disorders and the best approaches to treatment. Indeed, these issues assume added importance, since it has been found that the occurrence of depression in schizophrenia has often been associated with worse outcome (5), impaired functioning, personal suffering (6), higher rates of relapse or rehospitalization (7–10), and even suicide (8, 11, 12)—a tragic event that terminates the lives of an estimated 10% of patients with schizophrenia (11, 13). This article considers our current conceptualizations of depression-like symptoms in patients with schizophrenia, documents their common occurrence, and reviews the differential diagnosis of conditions that such symptoms might reflect. It also presents a potential integrating model that may facilitate the understanding of depression in at least some individuals with schizophrenia. Last, this article explores the implications for treatment as we enter a new era in schizophrenia pharmacotherapy occasioned by the advent of the so-called atypical antipsychotic agents.
Depression in Schizophrenia
Affect, Symptom, or Syndrome?
Some of the confusion attending the term “depression” in schizophrenia is attributable to the question of whether it is the affect of depression, the symptom of depression, or the syndrome of depression that is being considered. This confusion is not limited to patients with schizophrenia, of course, but it certainly has confounded the schizophrenia literature. Depression as an affect reflects an individual’s momentary mood state on the subjective experience spectrum from happiness to sadness as he or she interacts with his or her internal and external environments. It is not, in itself, pathological as long as it is situationally appropriate (e.g., a touching movie may elicit sad affect). Depression as a symptom is a sad mood state that causes a person distress. It is an unwanted painful feeling and can be a source of complaint. However, it is not necessarily enduring or accompanied by other features that are required for the diagnosis of the syndrome of depression. The depression syndrome is a complex of features that typically involves the symptom of depression but also includes cognitive and vegetative features such as pessimism, guilt, impaired concentration, lack of confidence, loss of interest or pleasure, and disturbances in sleep, appetite, and energy level. Unfortunately, the literature on depression in schizophrenia is often imprecise as to whether the affect, symptom, or syndrome of depression is involved, and these three meanings have often been employed loosely and interchangeably. The literature needs to be read carefully in this regard, and, most important, patients need to be listened to closely to understand the
Am J Psychiatry 157:9, September 2000
Therefore. at least some meaningful point prevalence of depression was observed in each study in which it was assessed. differentiating these two states can sometimes be difficult if patients lack the interpersonal communication skills to articulate their internal subjective states well. Another study found a positive relationship between haloperidol plasma levels and depressive symptoms in the context of a positive association between extrapyramidal symptoms and depressive symptoms (40). Various pharmaceuticals used in medical treatment such as β blockers. 47–49). The 7% observation involved a single cross-sectional assessment of a rating scale item in chronically hospitalized patients with schizophrenia in whom an effort was made to distinguish depression from negative symptoms (20). Investigations have varied considerably in terms of the definitions employed for schizophrenia and depression. cannabis. Rates of Occurrence of Depression in Schizophrenia Over three dozen published studies have examined rates or dimensions of depression in schizophrenia. Symptom factor analysis studies that have attempted to go beyond the basic positive/negative symptom distinction by expanding to five dimensions have identified a depression or anxiety/depression factor. of course. And studies examining schizophrenic patients with and without depression found that these two groups did not show any differences Am J Psychiatry 157:9. whereas those studies that used fewer dimensions have not (15–18). However. These include cardiovascular disorders. or motivation along with psychomotor retardation and impaired ability to concentrate are relevant overlapping features. Unfortunately. 42–46). 14–18). cancer. Blunted affect. dopamine blockade by a neuroleptic drug could theoretically lead to anhedonia and. The modal rate of depression for all reports was 25% (3. neurological. and one study found more anhedonia and depression in maintenance-phase schizophrenic patients who were taking neuroleptics than in others who were not (33). 33). for example. the observed interval. Differences in definition may account for some of the discrepancies in the reported occurrence rates and treatment responses of depression in schizophrenia. are dependent on exactly what symptom items are employed. It is also important to note that the discontinuation of two very commonly used legal substances. energy. These have been reviewed elsewhere (4. or narcotics can contribute to depression either on the basis of acute use. substances such as alcohol. and this situation has contributed to the creation of the proposed syndromal definition “postpsychotic depressive disorder of schizophrenia” in Appendix B of DSM-IV (pp. sulfonamides. depression. 4. Recent “smoke-free” and “decaf” policies on many inpatient units may have led to higher rates of this form of depression. Used or abused 1380 . Diminished interest. 23). Nevertheless. September 2000 Differential Diagnosis of Depression in the Course of Schizophrenia Medical/Organic Factors A number of medical/organic factors can present as depression in patients with schizophrenia (21). pleasure. autoimmune diseases. or discontinuation. and in this way initial assumptions can impact results substantially. and impairments of quality of life related to neuroleptic-induced dysphoria have been reported (41). anemia. antineoplastics. can lead to withdrawal states that potentially mimic depression (22. the preponderance of controlled-study evidence tends to refute the proposition that neuroleptic medication is regularly responsible for the development of depressive states in schizophrenia (4 . 711–712). nicotine and caffeine. and the patient status. Neuroleptic-Induced Dysphoria Dopamine synapses are involved in brain pathways mediating “reward” (32. Nevertheless. The 75% figure reflected at least one positive assessment of depression according to either of two criteria (one syndromal. barbiturates. perhaps. cocaine. Results of factor analyses. and indomethacin can cause depression as a side effect. the assessment methodology. the other based on a rating scale score) among patients with first-episode schizophrenia evaluated longitudinally on a weekly to monthly basis for up to 5 years (19). pulmonary infections. Indeed. Prospective observations that have followed schizophrenic patients through the treatment of acute psychotic episodes suggest that depressive symptoms were present before the neuroleptic was given and tended to subsequently subside (20. and metabolic. Negative Symptoms of Schizophrenia The negative symptom syndrome of schizophrenia overlaps with the syndrome of depression in a number of important respects (24–27). 6. Proportions of patients manifesting depression ranged from a high of 75% to a low of 7%. nonsteroidal anti-inflammatory drugs. 14). Studies that compared patients with schizophrenia who were being treated with neuroleptic medications versus those who were not did not find that neuroleptic-treated patients manifested more depression (20. a state of dysphoria is commonly described by neuroleptic-treated patients (34). and endocrine disorders. sedative hypnotics. suggests negative symptoms.DEPRESSION IN SCHIZOPHRENIA type of “depression” that they are experiencing. whereas distinct blue mood or cognitive features such as guilt or suicidal thoughts suggest depression. Depression can also accompany the discontinuation of other prescribed medications such as corticosteroids and psychostimulants. certain other symptoms may be more distinguishing (28–31). 42). chronic use. other antihypertensive agents. a number of older anecdotal reports have suggested a link between neuroleptic use and depression (35–39). 7.
which has resulted in variations in the boundary between schizoaffective depression and depression in schizophrenia. Patients with akathisia behave “as if their starter motor won’t stop” and often experience this state as substantially dysphoric (59. schizoaffective disorder has been defined differently according to various diagnostic schemes (74–76). making it virtually indistinguishable clinically from depression. Patients themselves may attribute this effect to “laziness. especially when depression follows closely after a stressful event or exacerbation of schizophrenia (3. However.” and they consequently appear to lack spontaneity. Anxiety.SAMUEL G. can easily be confounded with depression (59). This definition would include many of the other defined categories in this article. 20. Prodrome of Psychotic Relapse Investigations into the course of psychotic decompensation in schizophrenia have frequently noted the appearance of depression-like symptoms (9. Reactions to Disappointment or Stress Reactions to disappointments. DSM-IV now suggests that the term “postpsychotic depression” be used to describe depression that occurs at any time after a psychotic episode in schizophrenia—even after a prolonged interval. such as holding a conversation or participating in activities. often lasting only a couple days to a couple weeks. schizoaffective disorder refers to patients in whom a full affective syndrome coincides with the florid 1381 . one biological possibility is that schizophrenia may represent a basic disorder of dopamine regulation (55) in which “brittle” patients are vulnerable to dopamine storms (psychosis) and droughts (negative symptoms). The appearance of a depression-like state as a prodrome of a new psychotic episode is a short-lived phenomenon. thereby possibly contributing to the impression of neuroleptic-induced depression. 64). “Postpsychotic Depression” In earlier times. As with akinesia. 63. 10. Indeed. this side effect leads to exclusion from much of what is normal in life. lasting hours. Blue mood can also accompany this condition. Such reactions are of two types: acute and chronic. these last longer and are apt to be more difficult to distinguish from other forms of depression. in signs or symptoms of early psychotic decompensation. schizophrenic patients who experience less of a sense of control regarding their illness (one of the hallmarks of demoralization) have been found to be more likely to experience depression (10).” experiencing guilt or shame. however. 50–54). akathisia has seldom been considered as a possible confound in studies of depression in schizophrenia. most studies of depression in neuroleptic-treated patients have not adequately considered this form of akinesia as a potentially confounding factor. Indeed. September 2000 Schizoaffective Depression The term “schizoaffective disorder” was first used in the early 1930s to describe patients showing an overlap of features of schizophrenia and affective illness (73). before being superseded by more prominent and definitive psychotic symptoms. Unfortunately. Nevertheless. Patients with this form of akinesia may or may not have the classical parkinsonian feature of decreased accessory motor movements. they act “as if their starter motor is broken. Chronic reactions to disappointment or stress have also been termed the demoralization syndrome (65–67). involves the initiation or maintenance of motor behavior. a sense of loss or powerlessness. SIRIS in neuroleptic doses or blood levels (8. In DSM-IV. Neuroleptic-Induced Akathisia Akathisia is another extrapyramidal side effect of neuroleptic treatment that. Neuroleptic-Induced Akinesia Rifkin et al. further blurring the distinction from other forms of depression. the administration of more than the minimum required neuroleptic (dopamine-blocking) medication could exacerbate negative symptoms. such as hypervigilance. in subtle presentation. Since so much of human interchange. cal connection between that event and a mood change. 45. or at most weeks. such an episode might belong in the previous category. An acute reaction to disappointment or stress is suggested by the parallel history of a recent compatible event and is sometimes validated by the patient making a psychologiAm J Psychiatry 157:9. or awareness of psychotic symptoms or psychological deficits can certainly present as or contribute to depression. 62). days. Demoralized patients with extended histories of disappointment or failure can also develop the conviction that a useful or satisfying life is impossible. akathisia has been associated with both suicidal ideation and—perhaps as a consequence of a general tendency toward motor action—suicidal behavior (61. or the overinterpretation of perceptions or events. By definition. possibly as a primary issue (58). 57) and Van Putten and May (58) went beyond the original “large muscle stiffness” definition of akinesia to describe a more subtle but equally debilitating extrapyramidal side effect of neuroleptic treatment involving impaired ability to initiate and sustain motor behavior. Acute reactions are generally brief. and may be responsive to supportive interventions or counterbalancing positive experiences. Over time. withdrawal. Demoralization is important to diagnose because it may be more responsive than other depressed states to appropriately targeted psychosocial interventions. perceptual disturbances. the term “postpsychotic depression” was used to describe a dysphoric state that immediately followed a psychotic episode (3). Clues to the underlying circumstance of psychotic relapse may be found. (56. In the sense that this was reactive to disappointment or stress. 68–72). In this situation. and shame commonly accompany dysphoria in this situation. guilt. 60).
Second. during which many detailed descriptions contributed to our understanding of the natural history of schizophrenia. Subsequently. It might also help explain the finding that maintenance antidepressant treatment. The descriptive diagnosis of schizoaffective disorder. abusive. they might circumvent the mechanism of neuroleptic-induced dysphoria that could contribute to the depression syndrome. which form the basis of our current recognition and understanding of this condition. 87–90). Since akinesia and akathisia figure prominently in the differential diagnosis of what appears as depression in schizophrenia. poor prenatal nutrition. atypical antipsychotic agents have a greatly reduced extrapyramidal side effect profile (82–86).g. In this Am J Psychiatry 157:9. The central notion is that vulnerability to schizophrenic psychosis occurs on a continuum in the population.. and debate continues as to whether schizoaffective disorder should be considered a type of schizophrenia. although this. of course. atypical antipsychotics have frequently been reported to be superior to standard neuroleptics in the treatment of negative symptoms (83–86. It was during this second era that most studies of “depression in schizophrenia” were undertaken. atypical antipsychotics may lead to superior outcomes for patients with schizophrenia. the depression-like symptoms observed early in the course of some psychotic decompensations. If this is the case. there is a small. notably. as suggested by quality-of-life measures (97. insomnia. a reasonable percentage of manifest psychotic episodes could be precipitated by depressive epis od es in i n di vid u al s o the r wise o n l y m o dera te ly vulnerable to psychosis. Either through effects on negative symptoms or by some other means. from a tiny fraction of persons with such a strong vulnerability that psychosis is virtually inevitable to the overwhelming majority of the population in whom the vulnerability is so slight that the risk of psychosis is virtually negligible. 91–96). or an erroneous concept altogether. almost all patients were treated with these agents. both acutely and in routine maintenance. also seemed to reduce their rate of psychotic exacerbations (81). more longitudinal psychic stresses (such as chaotic. September 2000 1382 . hormonal changes. After neuroleptic agents were introduced in the 1950s. yet meaningful. Certainly depression is a highly stressful state psychologically. schizophrenia. however. There are several reasons to suspect that schizophrenia treated with atypical antipsychotics may prove to be at least a somewhat different condition than schizophrenia treated with conventional neuroleptics from the point of view of depression. and many relevant stresses have been described. A new and at least somewhat milder condition resulted: neuroleptic-treated schizophrenia. a domain on a continuum between schizophrenia and affective disorder. a distinct entity. birth injuries. and it is possible that it is stressful in relevant biological ways as well (e. It is provocative to speculate that the activation of an affective diathesis. The first era was the preneuroleptic epoch. a co-occurrence of two distinct diatheses. Third. neurotransmitter effects). it might help to explain some of the “depression” seen in the course of Depression in Schizophrenia and “Atypical” Antipsychotics The advent of so-called atypical antipsychotic agents may be ushering in a new or “third” era with regard to dealing with schizophrenia. could act as a sufficient stressor precipitating psychosis in people with otherwise modest vulnerabilities. First. sometimes one and sometimes the other. which can sometimes appear similar to depression. and lack of opportunity to develop adequate compensating coping skills are examples of psychosocial stressors. 80). this issue alone could be responsible for a notably different expression of depression in schizophrenia.DEPRESSION IN SCHIZOPHRENIA psychotic syndrome but who also have substantial periods of psychosis in the absence of an affective syndrome. or high “expressed emotion” environments). a type of affective disorder. portion of individuals who could become psychotic if stressed enough but who could also survive without psychosis if not sufficiently stressed. This hypothesis is consistent with the observation that dysphoria is associated more with positive symptoms than with negative symptoms in schizophrenia (79. still needs to be confirmed by appropriate careful investigations. it quickly became apparent that a remarkable curtailing of many dramatic psychotic manifestations was possible. The stress in this model can be biological or psychosocial. And since within the vulnerability continuum there are many more people with moderate than with extreme vulnerabilities. such as depression. and childhood head trauma would all be examples of early-life biological stressors. 98). 78) depicts the psychosis of schizophrenia as a final common path of neuropsychiatric decompensation. This definition does not resolve the etiology or pathophysiology of the condition. administered for the purpose of averting depressive relapses in schizophrenic patients with histories of syndromal postpsychotic depression. The Stress-Vulnerability Model as a Potential Integrating Concept The well-known stress-diathesis model of schizophrenia (77. Substance abuse is an example of a biological stressor occurring more proximally to a first or subsequent psychotic episode. including. since atypical agents seem to rely much less exclusively on dopaminergic blockade for their therapeutic activity (83. even if many negative or cognitive symptoms persisted. has value in defining phenomenologically an interesting patient group for which biological studies and clinical trials can be undertaken. In between. Intrauterine viral infection. Traumatic interpersonal experiences.
September 2000 of the studies in Table 1 used haloperidol as a comparison medication. depression associated with the prodrome of psychotic relapse might possibly be reduced. Treatment Strategies A rational approach to treating depression in schizophrenia flows from considering the differential diagnosis. 103). that olanzapine. risperidone. the controlled observations to date are intriguing with regard to potentially reduced rates of depression-like morbidity among schizophrenic patients receiving atypical antipsychotics. presented data suggesting that risperidone may be inferior to haloperidol in terms of BPRS anxiety/depression factor improvement. Obviously. the first consideration concerning a newly emergent depressive reaction in schizophrenia is whether it is a transient reaction to disappointment or stress or the prodrome of a new psychotic episode. 130). Several of these suggest a benefit for atypical antipsychotic agents in this regard. Twelve of the 13 present evidence. especially since it represents such an important negative outcome. 122–129). of various strengths. as summarized in Table 1. although imperfect. Last. However. in this context. both acute and chronic reactions to disappointment or stress may be reduced. It is relevant to note. or ziprasidone may have an antidepressant spectrum of activity in patients with schizophrenia or schizoaffective disorder. and atypical antipsychotic agents goes beyond the scope of this article. 100–102).SAMUEL G. SIRIS event. Further research is needed to clarify the shape and size of such an effect and to probe its possible mechanisms. 115–119). The most prudent initial response is to increase surveillance and provide additional nonspecific support. the smallest of the group. however. One trial (105). Altogether. a number of anecdotal reports also suggest that the atypical antipsychotics have superior antidepressant properties or. although studies have not been specifically designed to tease this out definitively. it is not unreasonable to speculate that suicidality can still serve as a logical. eight Am J Psychiatry 157:9. It is also possible that at least some atypical antipsychotic agents (so far demonstrated clearly only for clozapine in the treatment of refractory schizophrenia) may be superior to standard neuroleptics in the treatment of psychosis itself (93. Whether this result has to do with the relatively high dose range of risperidone employed (as much as 20 mg/day) or the lower dose range of haloperidol (as low as 2 mg/day) compared to the other studies is unclear. Suicidality is not a direct measure of depression. 96. Indeed. schizophrenia. Another mechanism whereby psychotic relapse may be averted through atypical antipsychotic use is by means of better medication compliance (95. or are reanalyses of. 121). with but a single study suggesting the contrary (105). that extrapyramidal side effects of haloperidol created a spurious impression of superior antidepressant activity for the atypical antipsychotics in these studies is lessened by the sophisticated path-analysis examination in the largest of the studies (95. Nevertheless. One study suggested that olanzapine was superior to risperidone in alleviating depression (71). 86. and muscarinic sites as well as α1-noradrenergic and histamine-1 receptor sites) suggest a variety of potential mechanisms through which atypical antipsychotics might exercise antidepressant effects (107. Table 1 reviews the controlled studies of atypical antipsychotic agents that make reference to the issue of depression. The final two studies in Table 1 present evidence suggesting that suicidality may be reduced in patients receiving clozapine. Thirteen of the studies in Table 1 either are. and two studies found ziprasidone to be superior to placebo (83. that conventional neuroleptics themselves have been found to have at least some degree of antidepressant activity (42. it is possible that atypical antipsychotic agents have direct antidepressant activity on their own. 109). 107). The broad array of affinities for receptor sites attributable to the novel atypical antipsychotic agents (including a wide array of 5-hydroxytryptamine [5-HT]. but it would be premature to conclude that this is the key or exclusive site of action. If this is the case. combinations of any or all of these effects could potentially be responsible for more favorable depression profiles in patients treated with atypical antipsychotics versus conventional neuroleptics. 85. Useful clues in this area may also be gleaned from the existing experience involving the use of tricyclic antidepressants as adjunctive agents in the treatment of depression in schizophrenia (14). An extended consideration of mechanistic biochemical issues concerning depression. The possibility. dopamine [other than D2]. 107. it may be features of agitation or excitement within the depression syndrome that may be particularly helped by atypical antipsychotics as well (120. proxy for depression in schizophrenia. Suffice it to say that there are many differences in receptor level activity among the different atypical antipsychotic agents that may prove to be relevant to their eventually being found to have differing clinical antidepressant profiles. perhaps particularly in patients with agitated depression. Interest in both depression (131) and schizophrenia (132) has focused on the 5-HT2 binding site. Excluding organic etiologies. antisuicidal properties when compared with conventional neuroleptics (87. 99). perhaps on the basis of a more favorable side effect profile (83. No published study could be found that tested the activity of quetiapine in this regard. In addition to the studies cited in Table 1. and more research is needed. and other factors such as psychotic disorganization or terror can also be associated with self-destructive behavior in this population. They therefore should not necessarily be considered to be a homogeneous group of agents nor should the effect—or lack of effect—found with one agent necessarily be assumed to apply to other atypical agents. prospective randomized trials. in the case of clozapine. A transient reaction to disappointment or stress will soon 1383 .
(109) 1996 and 1998 Inpatients with acute exacerbation of schizophrenia (N=335) 1998 Tandon et al. Observations of “Depression” in Schizophrenic Patient Groups From Controlled Studies Involving Treatment With Atypical Antipsychotic Agents Study Azorin (104) Year 1995 Patient Groupa Inpatients with schizophrenia (N=388) Study Design Duration Comment At optimal risperidone dose (6 mg/day). 6 weeks placebo-controlled comparison of 40 and 80 mg b. 10. 2–20 mg/day Randomized.03).0002) 3.10–0.d. (94) 1995 Inpatients with schizophrenia (N=523) Peuskens (82) 1995 Inpatients with chronic schizophrenia (N=1.6%) than with risperidone (4.05) Randomized. b Obtained from the Positive and Negative Syndrome Scale (113). “Apparent sadness” item alone also favored olanzapine over haloperidol (p<0. and haloperidol.11)c No statistically significant difference between any of the risperidone doses and haloperidol for scores on the BPRS anxiety/depression clusterb. 5–20 mg/day (mean=11. improvement with ziprasidone.008) was seen with olanzapine. (110) Meltzer and Okayli (111) Walker et al.5%. and 5. 15 mg/day. Path analysis determined that 57% of the antidepressant response to olanzapine was through a direct effect on mood. 4–12 mg/ day. the therapeutic effect on negative symptoms found for risperidone (p=0. but did not contribute statistically significantly to. approxiphrenic or schizoafmately 500 mg/day) fective inpatients at initial evaluation (N=420) Evaluation of clozapine. and haloperidol.05) or haloperidol-treated (p<0.001) and significantly greater 50% or more response rate after 3 weeks (p=0.001) Patients treated with 10 and 15 mg/day of olanzapine improved significantly more than placebo-treated patients on BPRS anxiety/ depression factor (p<0. 12. (112) 1997 and 1999 1995 1998 Schizophrenic or schizoaffective inpatients with acute exacerbations (N=139) Schizophrenic or schizoaffective inpatients with acute exacerbations (N=302) Evaluation of clozapine Chronic schizo(average dose. of ziprasidone 6 months During clozapine treatment of neurolepticresistant patients. and 16 mg/day of risperidone Randomized. (106) and Tollefson et al.05) In a subset of patients with scores ≥14 at baselined.001). 6 weeks placebo-controlled comparison of haloperidol. 2–20 mg/ day. and 16 mg/ day of risperidone Same as above 8 weeks Möller et al.362) Inpatients with schizophrenia (per ICD-9) (N=62) Inpatients and outpatients with schizophrenia or schizoaffective/ schizophreniform disorder (per DSM-IV) (N=339) Inpatients and outpatients with schizophrenia or schizoaffective/ schizophreniform disorder (N=1. (107) 1997 and 1998 Randomized. whereas patients treated with haloperidol or 5 mg/day of olanzapine did not Ziprasidone at 120 mg/day was more effective than placebo in improvement of BPRS depression cluster (p<0. 6. double-blind. 8 weeks placebo-controlled comparison of haloperidol.3% versus 12. 160 mg/day. (108) Keck et al. 86). double-blind. double-blind comparison of risperidone. (71) 1993 8 weeks 1997 and 1999 28 weeks Tollefson et al. improvement with olanzapine was greater (p=0. d Assessed with the Montgomery-Åsberg Depression Rating Scale (114).i. 4 weeks placebo-controlled comparison of 40 and 120 mg/day of ziprasidone Randomized. and 15 mg/day of olanzapine Randomized. the decrease in mean Brief Psychiatric Rating Scale (BPRS) anxiety/depression scoreb was greater than that seen in the placebo-treated (p<0.30) a Diagnoses per DSM-III-R unless otherwise indicated. and 2.05) Significantly greater improvementd (p=0.004). 8. there was a significant (mean= decrease in suicidality (p<0. 1384 Am J Psychiatry 157:9. 10–20 mg/day 8 weeks Ceskova and Svestka (105) Tran et al.02) Schizophrenic patients comprised 82% of the group. 20 mg/day. For patients with scores ≥16 at baseline.2%) (p=0. double-blind 6 weeks comparison of olanzapine. (95) and Tollefson et al. c Analysis of data from the North American Risperidone Study (85. 95% confidence interval=0. double-blind. September 2000 . was approximately double that of placebo (31. (91) and Tollefson et al. 10 mg/day. and olanzapine. 10. double-blind comparison of haloperidol. double-blind comparison of risperidone.01) patientsc Change in depressive symptoms (BPRS anxiety/ depression subscale scoreb) was in the direction of. 5–20 mg/day (mean=13. and 1. National Registry of various doses Clozapine Recipients 1991–1993 Randomized. Post hoc evaluation of depression clusterb revealed that olanzapine had a higher categorical improvement rate of ≥7 points (p=0.17.5 years) Various Mortality rate from suicide was lower in current clozapine users than in past users (rate ratio=0. change in BPRS anxiety/depression factor favored the haloperidol-treated patients (p<0. double-blind.2).996) Randomized.8) Beasley et al. Rate of suicide attempts lower with olanzapine (0. Olanzapine response to depression itemb superior to risperidone response (p=0.DEPRESSION IN SCHIZOPHRENIA TABLE 1.6%) (p<0. (83) and Daniel et al. 4. suicide attempt rate fell to 7 years from 25% to 3.05). although improvement tended to be greater in the groups given 4 and 8 mg/day of risperidone At 8 weeks.
Additionally. 134) or anti-negative-symptom action (135). although the literature is sparse (142). Again. In the latter case. If the episode of depression persists in a patient already being treated with an atypical antipsychotic. However. But this does not mean that they are not useful. if there is leeway to accomplish this safely. 14. which has at least a modest degree of parkinsonian side effects in the higher dose range (88). skill-building. Most reports concerning the use of lithium in schizophrenia have focused on its acute use during psychotic exacerbations rather than its extended use during maintenance-phase treatment (138. 14). 136–139). The indicators most frequently cited in the literature as being of favorable prognostic significance for lithium response in schizophrenia have been excitement. 148–150). however. although it may well be useful. confidence. problem-solving techniques. since it is possible that it has its own antidepressant activity (27. however. 152). SIRIS resolve spontaneously. It is certainly plausible. and self-esteem and interventions that contribute to real-life success experiences may be quite beneficial as well. and family interventions designed to minimize excessive expressed emotion can be helpful (155). Appropriately controlled studies of psychosocial interventions are. psychoeducation. the existing literature gives less guidance. either as an extrapyramidal side effect (akinesia or akathisia) or as a form of direct neuroleptic-induced dysphoria. and euphoria. The study that was most positive involved full syndromal depression criteria and continued antiparkinsonian medication throughout the antidepressant trial (136). a benzodiazepine. Substituting one atypical antipsychotic agent for another is an additional possibility. 141). any discussion of treatment strategies for depression in schizophrenia is incomplete without consideration of psychosocial interventions. that selective serotonin reuptake inhibitor (SSRI) antidepressants would be useful as well. Other favorable prognosticators mentioned for lithium response in schizophrenia are the presence of previous affective episodes. and trazodone (151) in Am J Psychiatry 157:9. and an incipient psychotic episode will soon declare itself. Anticholinergic antiparkinsonian medication may be an interesting option as well. 6. although definitive trials have not been published. MAOIs (141. especially if the antipsychotic agent is risperidone. In antipsychotic-treated schizophrenic patients who are not flagrantly psychotic. It is of further interest that there have been some encouraging results involving adjunctive SSRIs (140. especially in conjunction with risperidone for the same reason. 2) introduction or upward titration of an antiparkinsonian medication (likely to be useful for akinesia but less likely for akathisia). or 3) substitution of an atypical antipsychotic for the conventional neuroleptic. is heterogeneous. although the focus of treatment discussed in this article has been primarily pharmacologic. 141. and an overall episodic nature to the clinical course (154). If an episode of depression persists in a patient treated with a conventional neuroleptic. There are three ways that such a situation could be approached: 1) neuroleptic dose reduction. lithium may be a useful adjunct in at least some cases of depression in schizophrenia. depression is well known to occur during the course of schizophrenia in many patients and contributes substantially to the morbidity—even mortality— of this disorder. Also of interest is that. a family history of affective illness. Adjunctive monoamine oxidase inhibitors (MAOIs) might also be useful for depression in schizophrenia. of course. Most of the literature supportive of this intervention has focused on conventional neuroleptic-treated outpatients receiving adjunctive tricyclic antidepressants (4. There is little doubt that appropriately applied psychosocial strategies. and some early results support this (140. depressive symptoms have occasionally been suggested as features indicative of a favorable adjunctive lithium response in schizophrenia (153). September 2000 double-blind trials treating negative symptoms in schizophrenia. overactivity. Strategies that foster hope. No prospective randomized study has yet been published. an anticholinergic antiparkinsonian agent would not be likely to be a felicitous choice in a patient receiving clozapine. however. including atypical antipsychotic agents. Conclusions In summary. Nevertheless. Finally. the question next arises whether the neuroleptic medication is responsible for the depression-like symptoms. persisting episodes of depression that do not respond to antiparkinsonian agents may respond to the addition of an adjunctive antidepressant medication (4. dose reduction is a possibility if there is leeway for this. “Depression” in schizophrenia. 143–147). the increased surveillance will allow the best chance for the new episode to be detected promptly and “nipped in the bud” by appropriate interventions with antipsychotic medication. involving an adjunctive antidepressant added to an atypical antipsychotic agent in depressed patients with schizophrenia. Additional investigations will be necessary to fully appreciate the place of depressive symptoms in the conceptualization of schizophrenia and the best uses of contemporary therapeutic options. ECT has not been specifically studied in the treatment of depression in patients with schizophrenia. or β blocker (the latter two being likely to be useful for akathisia ). notoriously complex and have not been carried out in a specifically depressed schizophrenic population. such as stress reduction. and the best approaches to its understanding and treatment are based on an appropriate differential diagnosis. 1385 . since the combined anticholinergic activity might lead to too great a risk of autonomic side effects.SAMUEL G. Antiparkinsonian medication is another option.
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