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Depression in schizophrenia: recognition and management in the USA
Schizophrenia Research 47 (2001) 185±197
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Depression in schizophrenia: recognition and management in the USA Samuel G. Siris a,*, Donald Addington b, Jean-Michel Azorin c, Ian R.H. Falloon d, Jes Gerlach e, Steven R. Hirsch f a
Continuing Psychiatric Services for Schizophrenia and Related Conditions, Hillside Hospital/Long Island Jewish Medical Center, 75-59 263rd Street, Glen Oaks, NY 11004, USA b Department of Psychiatry, Foothills Hospital, Calgary Alberta, Canada c Psychiatric Service, Sainte Marguerite Hospital, Marseille, France d Department of Psychiatry & Behavioral Science, University of Auckland, Auckland, New Zealand e Department of Psychiatry, St Hans Hospital, Roskilde, Denmark f Department of Psychiatry, Imperial College School of Medicine, London, UK Received 14 June 2000; accepted 1 August 2000
Abstract The recognition of depression as a distinct syndrome within schizophrenia is a relatively recent development. The International Survey of Depression in Schizophrenia was designed to evaluate current clinical practice and prescribing trends in the management of the depressive component of schizophrenia. A 48-item questionnaire, comprising ®xed-response questions and questions stimulated by case scenarios, was distributed to 37 513 psychiatrists in the USA. A total of 43 484 psychiatrists in Canada, Australia and 21 European countries also received the questionnaire. A total of 1128 US psychiatrists responded. Analysis of the data revealed that US psychiatrists identify symptoms of depression in approximately one-third of patients with schizophrenia, and largely appreciate the magnitude of the resultant burden on patients and their families. Responses to questions regarding treatment approaches and case scenarios demonstrated that the level of adjunctive prescribing of antidepressants in the USA is often higher than in other regions. Levels of awareness of depression in patients with schizophrenia and recognition of the need for effective management appear to be high among US psychiatrists. However, more than a quarter of these specialists rarely or never prescribe adjunctive antidepressant medications. Disparities in treatment approaches varying from the existing scienti®c evidence base underscore the need for further investigation into ways of optimizing the management of this serious coexisting condition. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Adjunctive therapies; Assessment; Depression; Diagnosis; Schizophrenia
1. Introduction
* Corresponding author. Tel.: 11-718-470-8138; fax: 11-718-470-6248. E-mail address: [email protected] (S.G. Siris).
The recent inclusion of postpsychotic depression as a diagnostic entity in ICD-10 and in the Appendix to DSM-IV is indicative of growing awareness of the importance of comorbid depression
0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(00)00135-3
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in schizophrenia. Descriptive and epidemiologic studies have documented a 25% modal occurrence rate of depressive-like syndromes during the longitudinal course of schizophrenia (Siris, 1995), and depressive symptoms have been noted in up to 81% of this population (Leff, 1990). Despite the high prevalence of depressive symptoms in schizophrenia, however, relatively little is known about their precise nature and course. We do know that the emergence of depressive symptoms in individuals with schizophrenia has been associated with poor outcome, increased medication usage, greater morbidity at discharge, increased hospital readmission rates, and early relapse (Glazer et al., 1981; Herz, 1985; Roy et al., 1986; Ram et al., 1995). In addition, comorbid depression may contribute to the disturbingly high rates of suicide among patients with schizophrenia: a 10% incidence of suicide in the ®rst 10 years of illness and a 15% lifetime incidence have been reported (Miles, 1977; Roy, 1990), and suicide is considered as the main cause of premature death in this population (Roy et al., 1983; Sartorius et al., 1987; Allebeck, 1989; Caldwell and Gottesman, 1990). Depression, and especially the associated symptom of self-reported or perceived hopelessness, is an important comorbidity factor in the assessment of suicide risk (Caldwell and Gottesman, 1990). Depressive symptoms are common throughout the various phases of schizophrenia. However, differential diagnosis is hampered by dif®culties associated with distinguishing between such symptomatology and certain features of schizophrenia (particularly negative symptoms) or effects of its treatment (principally akinesia) and also by the dif®culty of recognizing depression in the presence of ¯orid psychosis (Siris, 2000). The Calgary Depression Scale (CDS) was developed for the purpose of identifying depression speci®cally in schizophrenia (Addington et al., 1990). However, most of the existing literature is still based on less speci®c assessment measures, and it is unclear how much the CDS, or other scales for that matter, are used in routine clinical practice. The majority of reported controlled studies of antidepressants in the treatment of depression in schizophrenia have employed adjunctive tricyclic antidepressants (TCAs). This approach has demon-
strated some ef®cacy, particularly in outpatients who are not acutely or actively psychotic (Plasky, 1991; Siris, 1991, 1994, 1995; Siris et al., 2000). Although few data are available regarding continuation and maintenance treatment with adjunctive antidepressants, one report provided strong evidence of the value of maintenance treatment in patients with postpsychotic depression that responded favorably to initial adjunctive antidepressant therapy (Siris et al., 1994). However, the combination of TCAs and many conventional antipsychotics raises pharmacokinetic and pharmacodynamic concerns (Gram and Overo, 1974; Loga et al., 1981; Linnoila et al., 1982; Cook et al., 1986). The International Survey of Depression in Schizophrenia was therefore designed to assess how these considerations and others, regarding the recognition and management of depressive symptoms in patients with schizophrenia, are being handled by psychiatrists in contemporary practice, and what further light this might shed on the understanding and treatment of this condition. 2. Methods A mail survey approach was adopted in order to survey the widest possible clinician base [a review of the problems of designing such questionnaires and evaluating the responses is provided in Hall et al. (1982)]. The International Survey of Depression questionnaires were distributed in March/April 1997 to approximately 80 000 psychiatrists in 24 countries world-wide, including 37 513 in the USA The list employed for identifying US psychiatrists was supplied by a specialist mailing house (Walsh, UK). Due to the extensive size and coverage of the survey, follow-up of non-responders was not possible. The questionnaire comprised 48 questions in the form of: Fixed-response questions addressing: ² Demographics of the respondents ² Symptoms relevant to the diagnosis of depression in schizophrenia ² Evaluation measures Ð which used and how routinely?
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² Factors that prompt the prescription of antidepressant medication ² Treatment selection ² Treatment practice, duration and dose
Table 2 Nature of respondents' current practice
Questions stimulated by case scenarios:
Hospital Clinic-/of®ce-based Private State-run health service University-af®liated Managed care organization Veterans' affair
² Diagnosis in response to case parameters ² Initial management plan (selection of new treatments, modi®cation of current treatments, psychosocial measures) ² Response to a development in the scenario, e.g. emergence of treatment-resistant symptoms or suicidal ideation. 2.1. Data handling Data were double-entered and centrally checked for consistency and reliability. All data analysis was carried out using Questionnaire Processing System (QPS) software (MRS Ltd, Wallington, Oxford, UK). This paper focuses primarily on the responses of psychiatrists in the USA, although comparisons are made with the ®ndings in other regions. Papers including more detailed discussions of the results in Europe and among the international respondent database are currently in preparation.
USA (%)
All regions (%)
47 50 40 15 26 7 10
61 39 36 24 23 6 4
Canada, 7.9%; and Europe, 4.9%. In total, 3443 questionnaires were returned, representing a response rate of 4.3%. The geographic spread and demographic pro®le of respondents are shown in Table 1. Data presented in Table 2 demonstrate the broad spectrum of respondents' practice at the time of the survey. Fifty-eight per cent of US psychiatrists indicated that outpatients accounted for more than 50% of their main practice Ð a somewhat higher ®gure than the average of 46% for respondents from all regions. This discrepancy was consistent with the fact that respondents world-wide reported responsibility for an average of 128 outpatients, compared with an average of 147 outpatients assigned to each clinician in the USA.
3. Results
3.1. Reported prevalence of depression
Altogether, 1128 US psychiatrists responded to the survey, a 3.0% response rate. Response rates in the three other geographic regions were: Australia, 9.6%;
The US respondents reported recognizing symptoms of signi®cant depression in a mean of 33% of ®rst-admission patients with psychotic symptoms,
Table 1 Demographics of respondents to survey
Total replies (percentage of total) Composition of respondent population [male/female (%)] Date of graduation from medical school (%) Pre-1960 1960±1969 1970±1979 1980±1989 Post-1990 Not stated Proportion of schizophrenia patients in respondents' current practice (%)
USA
All regions
1128 (38) 76/23
3443 (100) 76/23
15 20 21 27 11 7 31
9 14 27 35 9 6 31
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38% of patients in acute relapse, and 29% of patients with chronic stable schizophrenia. These ®gures are similar to those reported by psychiatrists world-wide: 29, 34 and 28%, respectively. Depression was most commonly encountered during the later stages of schizophrenia, particularly as acute psychotic symptoms resolved (see Fig. 1). Observations among clinicians in the USA differed somewhat from those among respondents world-wide with respect to the nature of depression in schizophrenic patients. As shown in Fig. 2, 57% of US psychiatrists identi®ed depression associated with substance use/abuse as the type that encountered they most frequently, compared with a signi®cantly lower ®gure of 35% of psychiatrists world-wide. Regarding effects on personal or vocational functioning, 77% of US respondents expressed a belief that depression signi®cantly added to the morbidity burden experienced by their schizophrenic patients, while 68% regarded its impact on the patient's family as signi®cant or highly signi®cant. These ®gures are of a similar order to those indicated by psychiatrists world-wide (68 and 60%, respectively). However, US respondents claimed a higher incidence of depression among
the caretakers of patients with schizophrenia: 43%, compared with 36% reported by the overall responders sample. 3.2. Treatment approaches 3.2.1. Antipsychotic therapy When considering treatment selection, 43% of US psychiatrists indicated that their choice of antipsychotic therapy for ®rst-admission patients was often or always in¯uenced by the appearance of concurrent depressive symptoms. Similar ®gures also reported that such comorbidity often or always in¯uenced their selection of treatment for relapse patients (46%) and for those with stable schizophrenic illness (42%). Participants were subsequently asked to indicate their ®rst choice of antipsychotic in three different clinical situations (Fig. 3). This revealed signi®cant differences in prescribing practice, particularly on ®rst admission, as follows: 1. At ®rst admission of a patient with ¯orid psychotic symptoms and features of depression. Conventional antipsychotic agents were indicated as the
Fig. 1. Time course of depression in schizophrenia.
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Fig. 2. Nature of depression in schizophrenia.
®rst-choice approach by 45% of US respondents, while 50% preferred an atypical agent (5% did not indicate a preference). These ®ndings are in contrast to those among respondents world-wide,
who indicated a higher preference for conventional (61%) than for atypical (34%) products. 2. Acute relapse in a patient with a known diagnosis of schizophrenia or schizoaffective disorder
Fig. 3. First choice of antipsychotic agent in speci®ed situations. Key: empty box: conventional antipsychotic; gray box: clozapine; black box: other atypical antipsychotic.
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presenting with the return of predominantly positive symptoms plus features of depression. In this situation, 38% of US respondents opted for a conventional antipsychotic agent as their treatment of choice, compared with 55% with a preference for atypical alternatives (7% were non-speci®c or did not indicate a preference). Corresponding ®gures for the entire world-wide respondent database were 52 and 41%, respectively. 3. A patient with schizophrenia or schizoaffective disorder with predominantly negative symptoms. Nine per cent of US respondents selected a conventional antipsychotic agent (no speci®c agent identi®ed) as their ®rst choice for such a patient, 8% speci®ed clozapine, and 78% indicated a preference for an atypical agent (5% were non-speci®c or did not indicate a preference). Again, these statistics indicated a lower use of conventional antipsychotics than among psychiatrists worldwide (20%), and a higher use of atypical agents (76% world-wide). Grouping conventional antipsychotic medications on the basis of high, medium or low potency, medium- or low-potency agents emerged as the treatment of choice of 9, 10, and 4% of US respondents in each of the three above clinical situations, respectively. However, the selection of these types of agent by psychiatrists world-wide was somewhat higher at 18, 19 and 9%, respectively. 3.2.2. Antidepressant therapy US respondents reported adjunctive prescription of antidepressant plus antipsychotic medication to 38% of their inpatients with schizophrenia and 43% of outpatients. Prescription of antidepressants was more common among US respondents than among psychiatrists world-wide, for both inpatients and outpatients. Table 3 summarizes the factors and symptoms most likely to prompt the prescription of an antidepressant to patients with recent-onset depressive symptomatology. Psychiatrists in the USA and world-wide identi®ed the same three symptoms as being the most in¯uential; however, US respondents tended to place more emphasis on insomnia and tearfulness, whereas respondents world-wide attached a greater signi®cance to diurnal mood variation and guilt.
Several antidepressants were frequently prescribed by both US psychiatrists and psychiatrists in all regions, most notably ¯uoxetine (62 and 49%, respectively), sertraline (62 and 43%, respectively) and paroxetine (49 and 45%, respectively). However, wider variations were seen in the usage of other, less popular, agents. Treatments of choice selected by more than 10% of US respondents were: trazodone (18%), nortriptyline (18%), buproprion (16%), and venlafaxine (15%), while those identi®ed by more than 10% of psychiatrists from all regions were: amitriptyline (21%), ¯uvoxamine (15%), clomipramine (14%), venlafaxine (13%), imipramine (11%), and trazodone (11%). US respondents considered adjunctive use of an antidepressant with an antipsychotic agent to be of clinical bene®t in 53% of schizophrenic patients with comorbid depression. The corresponding ®gure for psychiatrists world-wide was 48%. Figures were also similar with respect to the belief that antidepressant therapy would be appropriate for patients with stable residual disease and predominantly depressive symptoms, even in the absence of concomitant antipsychotic therapy: 49% of US psychiatrists and 51% of respondents world-wide. Adjunctive antidepressant therapy was rarely or never prescribed for patients with schizophrenia by 28% of US respondents, compared with 33% of psychiatrists world-wide. The most frequently cited reasons (indicated by 25% or more of US psychiatrists who rarely/never prescribed) for this avoidance of adjunctive therapy are shown in Table 4. 3.2.3. Drug combinations and treatment duration Twenty-two per cent of US respondents indicated a preferred combination of antipsychotic and antidepressant, the most popular combination being that of an atypical antipsychotic agent and a selective serotonin reuptake inhibitor (SSRI) (selected by 48% of those with any preferences). This combination was also the most popular among respondents world-wide, being indicated by 30% of psychiatrists in all regions. Thirty-one per cent of US respondents named drug combinations that they would avoid (respondents were allowed to name more than one combination), with thioridazine (cited by 29% of those who
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Table 3 Factors and symptoms most likely to prompt conjunctive antidepressant therapy from US psychiatrists in schizophrenia patients with recentonset depression Factor (relative importance a)
Symptom (% b)
Family history of depressive disorder (4.37) History of frequent recurrent admissions (3.78) Recent loss or rejection (3.76) History of substance abuse (3.31) High level of stress in family/household (3.24) Unmarried/divorced (3.13) Living alone (3.10) History of poor compliance (3.04) Unemployment (2.94) First admission (2.90) Supervised living arrangements (2.89) High educational level (2.82) Good interpersonal and social skills (2.82) Poor interpersonal and social skills (2.82) Chronic schizophrenia (2.81) Male gender (2.48) Low educational level (2.47) Female gender (2.42) Family of high social class (2.40) Low stress levels in family/household (2.39) Family of low social class (2.32)
Suicidal ideation (72) Hopelessness (50) Low mood (48) Insomnia (37) Anhedonia (32) Tearfulness (32) Early morning wakening (31) Guilt (26) Diurnal mood variation (25) Weight loss (23) Loss of appetite (21) Psychomotor retardation (18) Loss of energy (16) Withdrawal (15) Self-deprecation (15) Poor concentration (8) Somatic symptoms (7) Hypersomnia (7) Psychomotor agitation (3) Paranoia (2)
a b
Mean value measured on a scale of 1±5, where 1 unimportant, and 5 very important. Percentage of psychiatrists identifying a symptom as being likely to prompt the prescription of antidepressants.
identi®ed combinations to avoid) and clozapine (19%) emerging as the most commonly cited antipsychotics in this context. The most commonly avoided antidepressants in any combinations were the TCAs (indicated by 67% of those who expressed a preference) and monoamine oxidase inhibitors (MAOIs, avoided by 14.5% of those who named combinations to avoid). Respondents world-wide reported avoiding combinations including thioridazine at a rate of 18%, those including clozapine at a rate of 17%, and combinations with TCAs and MAOIs at rates of 52 and 21%, respectively. Forty-four per cent of US respondents indicated that antidepressant therapy would take 2±4 weeks to produce clinical bene®ts when added to an antipsychotic agent, while 30% indicated that a period of 4±6 weeks would be required. A large proportion of these psychiatrists (39%) felt that treatment, once initiated, should continue for 6± 12 months if the patient showed a satisfactory response.
3.2.4. Electroconvulsive therapy Thirty-six per cent of US psychiatrists reported using electroconvulsive therapy (ECT) to treat patients with schizophrenia or schizoaffective disorder with depressive symptoms. This ®gure is somewhat lower than the reported world-wide usage of 42%. 3.3. Psychotherapy The use of psychotherapeutic approaches was generally higher than average among US respondents. Table 4 Reasons most frequently cited by US psychiatrists for rarely/never prescribing conjunctive antidepressant plus antipsychotic therapies X Risk of exacerbation of psychotic disorder X Depression considered to be part of the psychotic disorder and responsive to antipsychotic medication X Risk of drug interactions X Risk of unfavorable side-effects X Depression considered to be due to psychosocial factors and responsive to psychosocial strategies
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Fig. 4. Frequently used psychotherapeutic approaches.
Psychoeducation emerged as the most popular technique, with 76% of US respondents indicating frequent use of this approach, compared with 58% of respondents world-wide. Fig. 4 illustrates the proportion of US respondents who indicated frequent use of various psychotherapeutic approaches. 3.3.1. Case scenarios Participants were asked to indicate their ®rst- and second-line therapeutic strategies in three separate case scenarios: Case 1. A patient with schizophrenia, previously well controlled with conventional antipsychotics, presenting with signi®cant depressive symptoms in the presence of a relapse of acute psychotic symptoms. Case 2. A patient presenting with an acute relapse manifesting as ¯orid psychotic symptoms promptly remitting on usual antipsychotic medication, but in whom depressive symptoms emerge during the second week. Case 3. A previously well-controlled patient with schizophrenia presenting with recent-onset depressive symptoms in the absence of any change in positive or negative symptoms or parkinsonism
(assuming that the patient is compliant and that there is no substance abuse, medical disorder or psychosocial precipitant to the admission). The diversity of preferred treatment approaches to these case scenarios was broad, particularly with respect to the acute-relapse case (case 1). The most popular ®rst-line therapeutic approaches to this case among US psychiatrists (respondents were allowed to select more than one ®rst-line strategy) were: increasing the dose of antipsychotic agent (64%) (56% world-wide); adding an antidepressant (62%) (58% world-wide); increasing psychosocial support and observing (44%) (44% world-wide); and switching to an alternative atypical antipsychotic agent (31%) (26% world-wide). Second-line strategies varied widely, but the most popular response was to add an antidepressant (cited by 42% of US respondents, compared with 40% world-wide). Although variable, the most popular US and world-wide ®rst- and second-line treatment strategies in cases 2 and 3 (again, selection of more than one strategy was permitted) involved adding an antidepressant and/or increasing psychosocial support and observing the patient. The use of antidepressant therapy as a ®rst-line strategy was indicated by 62%
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of US respondents for case 1 (acute relapse), 64% for case 2 (rapidly emerging postpsychotic depression) and 80% for case 3 (chronic stable schizophrenia with emerging depression). These ®gures are higher than those indicated by respondents world-wide (58, 54, and 73%, respectively). 3.3.2. Diagnosis and assessment of depressive symptoms In order to gain an insight into routine patient diagnosis and assessment practices, participants were asked a series of questions regarding their use of speci®c interview systems, assessment instruments, and depression rating scales. Routine clinical practice use of speci®c interview systems for the diagnosis of schizophrenia was relatively low among US respondents (17%), with the vast majority (79%) of those who applied such instruments using the structural clinical interview for DSM-III-R (SCID). Sixteen per cent of respondents world-wide used speci®c interview systems, with 83% of these favoring the SCID. Twenty-three per cent of both US and world-wide respondents reported routine use of standard instruments to assess patients with psychosis. Systems most frequently employed in the USA (respondents were asked to indicate all instruments routinely used) were: the Abnormal Involuntary Movement Scale (AIMS) (employed by 60% of those US respondents who used instruments); Brief Psychiatric Rating Scale (BPRS) (56%); Hamilton Depression Rating Scale (HDS) (40%); Beck Depression Inventory (BDI) (39%); and the Positive and Negative Syndrome Scale (PANSS) (37%). Geographical variations were evident in the levels of usage of these instruments, most notable with respect to the AIMS, which was reported to be routinely used by 60% of US psychiatrists but only 30% of respondents worldwide. Twenty-®ve per cent of US respondents claimed routine use of depression rating scales as part of the clinical assessment of patients with schizophrenia admitted with a clear depressive component to their presentation. The most commonly cited methods were the BDI (52%), HDS (49%), and BPRS (29%). Only 7 and 1% of US psychiatrists reported Ê sberg Depression routine use of the Montgomery±A Rating Scale (MADRS) and the CDS, respectively.
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Worldwide, the same percentage (25%) of psychiatrists claimed routine use of depression rating scales in patients with schizophrenia with comorbid depressive symptomatology. The methods cited were as follows: HDS, 57%; BDI, 42%; BPRS, 23%; PANSS, 23%; MADRS, 19%; AIMS, 12%; and the Scale for the Assessment of Negative Symptoms (SANS), 10%. 3.3.3. Suicide Psychiatrists in the USA reported the lowest national suicide rates among patients with schizophrenia: only 14% reported one patient suicide or more in the year prior to the survey, although 15% of US psychiatrists failed to respond to this question. Depression was identi®ed as a signi®cant factor in the majority of suicide cases. Twenty-three per cent of respondents world-wide reported one suicide or more among their schizophrenia patients in the year leading up to the survey, while 16% failed to register a response. 4. Discussion The questionnaire response rate among US psychiatrists was relatively low (3.0%) and, due to the nature of the study, follow-up of non-responders was not possible. Nevertheless, a database of responses from 1128 psychiatrists in the USA is a considerable sample size. How representative these data are of the total population of all practising psychiatrists could be questioned, as respondents were likely to be those with an active interest in the area under consideration. The demographics of the sample do, however, appear to represent a reasonable cross-section of clinical practice. While the possible in¯uence of existing literature, educational experiences, and commercial marketing campaigns cannot be discounted, one of the values of the International Survey was the likelihood that opinions expressed by the respondents would re¯ect their personal `in the ®eld' experience, at least to a substantial degree. In addition, responses to stimulus material in the form of case scenarios paralleled the responses to earlier questions relating to diagnosis and treatment. In general, selected treatment options also correlated with responses to questions regarding
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prescription frequency, indicating internal consistency of responses. 4.1. Prevalence of depression Although the data from this survey must be viewed in the context of the limitations of the questionnaire approach by which they were obtained, they nevertheless broadly corroborate the data from previous prevalence surveys and indicate recognition of a substantial clinical burden of depressive symptomatology in schizophrenia (McGlashan and Carpenter, 1976). US clinicians reported encountering depressive symptoms in about one-third of their schizophrenic patients, and three-quarters demonstrated a good appreciation of the magnitude of the associated additional burden imposed on patients and their caretakers. The general agreement, with respect to the prevalence, course, and nature of depressive symptoms in patients with schizophrenia, observed internationally is noteworthy, since this establishes the scale of the problem and the recognized need to address it. The survey ®ndings point to a relatively high level of awareness among US psychiatrists of the impact of comorbid depression on patients with schizophrenia and their families, but it is unclear whether this re¯ects a more problematic course of depression in schizophrenia in the USA or simply demonstrates a greater sensitivity to the problem among this particular professional group. 4.2. Depression rating scales Approximately one-fourth of US respondents reported the routine use of depression-rating scales. For the most part, they utilized older depression rating scales that are not speci®c to schizophrenia (mainly the BDI and HDS). Only about 1% utilized the CDS, a relatively simple scale that is designed to differentiate depression from negative symptoms and extrapyramidal symptoms in subjects with schizophrenia (Addington et al., 1993, 1994). Interestingly, however, when psychiatrists were asked to identify the symptoms that most in¯uence their decision to prescribe an antidepressant, ®ve of the most commonly cited factors (suicidal ideation, hopelessness, low mood, diurnal mood, morning wakening) were among the eight speci®c items of the CDS.
4.3. Managing depression in schizophrenia Regarding the overall choice of antipsychotic agents, the majority of US respondents indicated that an atypical agent would be their ®rst-choice therapy in all three clinical situations presented. Conventional antipsychotics remained the treatment of choice for a large proportion of respondents, particularly for a ®rst-admission case, but, in comparison with the world-wide ®ndings, their popularity among US clinicians was limited. This ®nding is indicative of a move toward a wider prescription of atypical agents where readily available. The use of atypical antipsychotics may be stimulated, at least in part, by their reported superiority to standard neuroleptics in terms of the treatment of depressive symptoms in schizophrenia (Azorin, 1995; MoÈller et al., 1995; Tandon et al., 1997; Tollefson et al., 1997, 1998; Keck et al., 1998; Siris, 2000). Novelty and marketing efforts may be further factors in their popularity. US psychiatrists showed a relatively high tendency to treat depression directly in patients with schizophrenia. Bearing in mind the lower reported suicide rates in this region, it would seem reasonable to suggest that greater recognition of the importance of such comorbidity contributes to improved outcomes. Differences in clinical practice approaches to in- and outpatient populations might have been expected, as existing research literature indicates that adjunctive antidepressant use can be effective in schizophrenic outpatients with depression but does not support this approach in inpatient populations (Siris, 1995). However, the present study failed to reveal any such differences, suggesting that psychiatrists apply their judgement of best practice concerning the use of adjunctive antidepressants across all patients with schizophrenia with comorbid depressive symptoms, regardless of the setting. Notably, this pattern of practice seems to be at variance with the controlled observations that the addition of an antidepressant to the antipsychotic treatment of patients with acute psychotic schizophrenia or schizoaffective disorder may actually retard the antipsychotic response (Kramer et al., 1989). Clinical practice guidelines published by the American Psychiatric Association (1997) recommend that depressive symptoms occurring comorbidly with acute psychotic symptoms should only be treated
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after the psychoses have been treated with antipsychotic medications (MoÈller et al., 1995). These guidelines urge caution in the adjunctive use of antidepressants during the acute phase of the illness and alert psychiatrists to the possibility of an exacerbation of psychotic symptoms. Approximately half of the US respondents to the survey indicated that they would consider antidepressant use even in the absence of concomitant antipsychotic therapy Ð a result that is surprising since this represents an approach that is not supported by the bulk of the literature in this area (Siris et al., 1978; Siris, 1995, 2000; American Psychiatric Association, 1997). The responses to questions regarding treatment approaches and case scenarios demonstrated a considerable variation in treatment strategies, particularly on ®rst admission and regarding second-line approaches. It seemed likely that clinicians' own perceptions of the underlying cause of the depressive component formed the basis of the selected treatment approach. Regardless of this variability, prescription of an antidepressant was indicated by the majority of US respondents in all three case scenarios, particularly for depressive symptoms arising in patients with chronic stable schizophrenia. The approach advocated by the American Psychiatric Association is to prescribe antidepressant medication for depressive symptomatology that persists beyond, or emerges after, the remission of acute psychosis in patients with schizophrenia (American Psychiatric Association, 1997). In general, treatment is indicated where depressive symptoms satisfy the syndromal criteria for major depressive disorder or are suf®ciently severe to cause notable distress or interfere with patient functioning. In their responses to this survey, US psychiatrists appear to indicate that they are sometimes willing to treat symptoms of depression as well as the depressive syndrome with antidepressive agents and thereby go beyond the therapeutic indication supported in the research literature. They also go beyond the research literature when they indicate a willingness to use antidepressant medications as adjunct antipsychotic agents in schizophrenic patients who continue to manifest substantial psychotic symptomatology. This might retard antipsychotic ef®cacy, and more psychiatrist education may be required. Alternatively, favorable clinical experience may be guiding these psychia-
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trists, and more research may be indicated to see where this is the case. Similarly, most studies of antidepressants in this context have employed TCAs (Siris, 1991, 2000). This survey indicates that many psychiatrists appear to feel comfortable utilizing other classes of antidepressants or report a speci®c preference for an atypical antipsychotic combined with an SSRI. This may indicate another area where future controlled clinical trials may be valuably informative. However, perhaps dissuaded by concerns regarding the safety of combinations of TCAs with many conventional antipsychotic agents (Loga et al., 1981; Linnoila et al., 1982), more than a quarter of US participants in the survey reported rarely or never prescribing adjunctive antidepressant medications. They may have had different clinical experiences that now guide their practice and should be learned about, or, alternatively, they may bene®t from education concerning the potential bene®ts of adjunctive antidepressant medications in appropriately selected schizophrenic patients. 5. Conclusion The ®ndings of the International Survey of Depression in Schizophrenia suggest that a majority of US psychiatrists are highly aware of the impact and associated problems of depression in schizophrenia and actively use adjunctive antidepressant medications in its treatment. There remain, however, a signi®cant minority who perceive less of a depression burden in schizophrenia and rarely, if ever, utilize combination treatment with an antidepressant. Some of the most frequently employed adjunctive antidepressant treatments have yet to be fully evaluated in controlled trials, and it appears that their popularity is largely derived from ongoing anecdotal clinical experience. Further scienti®c guidance in this area is obviously required, and large-scale surveys of the kind reported here may provide a useful stimulus and help frame questions for this endeavor most fruitfully. Acknowledgements This survey was supported by an unrestricted
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educational grant from P®zer Pharmaceuticals Group, New York, USA. This work was presented, in part, at the 37th Annual Meeting of the American College of Neuropsychopharmacology, Las Croabas, Puerto Rico, on December 14, 1998, and at the 7th International Congress on Schizophrenia Research, Santa Fe, New Mexico, on April 17, 1999.
References Addington, D., Addington, J., Schissel, B., 1990. A depression rating scale for schizophrenics. Schizophr. Res. 3, 247±251. Addington, D., Addington, J., Maticka-Tyndale, E., 1993. Assessing depression in schizophrenia: The Calgary Depression Scale. Br. J. Psychiatry 163, 39±44. Addington, D., Addington, J., Maticka-Tyndale, E., 1994. Speci®city of the Calgary Depression Scale for schizophrenia. Schizophr. Res. 11, 239±244. Allebeck, P., 1989. Schizophrenia, a life-shorting disease. Schizophr. Bull. 15, 81±89. American Psychiatric Association, 1997. Practice guidelines for the treatment of patients with schizophrenia. Am. J. Psychiatry 154 (Suppl.), 1±63. Azorin, J.M., 1995. Long-term treatment of mood disorders in schizophrenia. Acta. Psychiatr. Scand. 91 (Suppl. 388), 20±23. Caldwell, C.B., Gottesman, I.I., 1990. Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophr. Bull. 16, 571±589. Cook, P.E., Dermer, S.W., Cardamone, J., 1986. Imipramine± ¯upenthixol decanoate interaction. Can. J. Psychiatry 31, 235±237. Glazer, W., Prusoff, B., John, K., Williams, D., 1981. Depression and social adjustment among chronic schizophrenic outpatients. J. Nerv. Ment. Dis. 169, 712±717. Gram, L.F., Overo, K.F., 1974. In¯uence of neuroleptics and benzodiazepines on metabolism of tricyclic antidepressants in man. Am. J. Psychiatry 131, 863±866. Hall, W., Weekes, P., Harvey, R., Andrews, G., 1982. A survey of practising psychiatrists' views on the treatment of agoraphobia. Aust. N. Z. J. Psychiatry 16, 225±233. Herz, M., 1985. Prodromal symptoms and prevention of relapse in schizophrenia. J. Clin. Psychiatry 46, 22±25. Keck, P., Buffenstein, A., Ferguson, J., Feighner, J., Jaffe, W., Harrigan, E.P., Morrissey, M.R., 1998. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 140, 173±184. Kramer, M.S., Vogel, W.H., DiJohnson, D., Dewey, D.A., Sheves, P., Gavicchia, S., Little, P., Schmidt, R., Kimes, I., 1989. Antidepressants in `depressed' schizophrenic inpatients: a controlled trial. Arch. Gen. Psychiatry 46, 922±928. Leff, J., 1990. Depressive symptoms in the course of schizophrenia.
In: DeLisi, L.E. (Ed.). Depression in Schizophrenia. American Psychiatric Press, Washington, DC, pp. 3±23. Linnoila, M., George, L., Guthrie, S., 1982. Interaction between antidepressants and perphenazine in psychiatric patients. Am. J. Psychiatry 139, 1329±1331. Loga, S., Curry, S., Lader, M., 1981. Interactions of chlorpromazine and nortriptyline in patients with schizophrenia. Clin. Pharmacokinet. 6, 454±462. McGlashan, T.H., Carpenter, W.T., 1976. Postpsychotic depression in schizophrenia. Arch. Gen. Psychiatry 33, 231±239. Miles, C.P., 1977. Conditions predisposing to suicide: a review. J. Nerv. Ment. Dis. 164, 231±264. MoÈller, H.-J., MuÈller, H., Borison, R., Schooler, N.R., Chouinard, G., 1995. A path analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients: a re-evaluation of the North American risperidone study. Eur. Arch. Psychiatry Clin. Neurosci. 245, 45±49. Plasky, P., 1991. Antidepressant usage in schizophrenia. Schizophr. Bull. 17, 649±657. Ram, R., Jandorf, L., Dixon, L., Bromet, E., 1995. Depressive syndromes in ®rst admission patients with schizophrenic disorders: the extent, phenomenology, correlates and change over six months. Schizophr. Res. 15, 1±2. Roy, A., 1990. Relationship between depression and suicidal behaviour in schizophrenia. In: DeLisi, L.E. (Ed.). Depression in Schizophrenia. American Psychiatric Press, Washington, DC, pp. 41±58. Roy, A., Thompson, R., Kennedy, S., 1983. Depression in chronic schizophrenia. Br. J. Psychiatry 142, 465±470. Roy, A., Schreiber, J., Mazonson, A., Picker, D., 1986. Suicidal behaviour in chronic schizophrenia: A follow up study. Can. J. Psychiatry 31, 737±740. Sartorius, N., Jablensky, A., Ernberg, G., et al., 1987. Course of schizophrenia in different countries: some results of a WHO international comparative 5-year follow-up study. In: Hafner, H., et al. (Eds.). Search for the Causes of Schizophrenia. Springer, Berlin, pp. 107±113. Siris, S.G., 1991. Diagnosis of secondary depression in schizophrenia: implications for DSM-IV. Schizophr. Bull. 17, 75±98. Siris, S.G., van Kammen, D.P., Docherty, J.P., 1978. The use of antidepressant edication in schizophrenia. Arch. Gen. Psychiatry 35, 1368±1377. Siris, S.G., 1994. Assessment and treatment of depression in schizophrenia. Psychiatr. Ann. 24, 463±467. Siris, S.G., Bermanzohn, P.C., Mason, S.E., Shuwall, M.A., 1994. Maintenance imipramine therapy for secondary depression in schizophrenia. Arch. Gen. Psychiatry 51, 109±114. Siris, S.G., 1995. Depression and schizophrenia. In: Hirsch, S.R., Weinberger, D. (Eds.). Schizophrenia. Blackwell Scienti®c, London, pp. 128±145. Siris, S.G., 2000. Depression in schizophrenia: perspective in the era of ªatypicalº antipsychotic agents. Am. J. Psychiatry 157, 1379±1389. Siris, S.G., Pollack, S., Bermanzohn, P., Stronger, R., 2000. Adjunctive imipramine for a broader group of post-psychotic depressions in schizophrenia. Schizophr. Res. 44, 187±192.
S.G. Siris et al. / Schizophrenia Research 47 (2001) 185±197 Tandon, R., Harrigan, E., Zorn, S.H., 1997. Ziprasidone: a novel antipsychotic with unique pharmacology and therapeutic potential. J. Serotonin Res. 4, 159±177. Tollefson, G.D., Beasley, C.M., Tran, P.V., Street, J.S., Krueger, J.A., Tamura, R.N., Graffeo, K.A., Thieme, M.E., 1997. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an
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international collaborative trial. Am. J. Psychiatry 154, 457± 465. Tollefson, G.D., Sanger, T.M., Beasley, C.M., Tran, P.V., 1998. A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia. Biol. Psychiatry 43, 803±810.
www.elsevier.com/locate/schres
Depression in schizophrenia: recognition and management in the USA Samuel G. Siris a,*, Donald Addington b, Jean-Michel Azorin c, Ian R.H. Falloon d, Jes Gerlach e, Steven R. Hirsch f a
Continuing Psychiatric Services for Schizophrenia and Related Conditions, Hillside Hospital/Long Island Jewish Medical Center, 75-59 263rd Street, Glen Oaks, NY 11004, USA b Department of Psychiatry, Foothills Hospital, Calgary Alberta, Canada c Psychiatric Service, Sainte Marguerite Hospital, Marseille, France d Department of Psychiatry & Behavioral Science, University of Auckland, Auckland, New Zealand e Department of Psychiatry, St Hans Hospital, Roskilde, Denmark f Department of Psychiatry, Imperial College School of Medicine, London, UK Received 14 June 2000; accepted 1 August 2000
Abstract The recognition of depression as a distinct syndrome within schizophrenia is a relatively recent development. The International Survey of Depression in Schizophrenia was designed to evaluate current clinical practice and prescribing trends in the management of the depressive component of schizophrenia. A 48-item questionnaire, comprising ®xed-response questions and questions stimulated by case scenarios, was distributed to 37 513 psychiatrists in the USA. A total of 43 484 psychiatrists in Canada, Australia and 21 European countries also received the questionnaire. A total of 1128 US psychiatrists responded. Analysis of the data revealed that US psychiatrists identify symptoms of depression in approximately one-third of patients with schizophrenia, and largely appreciate the magnitude of the resultant burden on patients and their families. Responses to questions regarding treatment approaches and case scenarios demonstrated that the level of adjunctive prescribing of antidepressants in the USA is often higher than in other regions. Levels of awareness of depression in patients with schizophrenia and recognition of the need for effective management appear to be high among US psychiatrists. However, more than a quarter of these specialists rarely or never prescribe adjunctive antidepressant medications. Disparities in treatment approaches varying from the existing scienti®c evidence base underscore the need for further investigation into ways of optimizing the management of this serious coexisting condition. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Adjunctive therapies; Assessment; Depression; Diagnosis; Schizophrenia
1. Introduction
* Corresponding author. Tel.: 11-718-470-8138; fax: 11-718-470-6248. E-mail address: [email protected] (S.G. Siris).
The recent inclusion of postpsychotic depression as a diagnostic entity in ICD-10 and in the Appendix to DSM-IV is indicative of growing awareness of the importance of comorbid depression
0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(00)00135-3
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in schizophrenia. Descriptive and epidemiologic studies have documented a 25% modal occurrence rate of depressive-like syndromes during the longitudinal course of schizophrenia (Siris, 1995), and depressive symptoms have been noted in up to 81% of this population (Leff, 1990). Despite the high prevalence of depressive symptoms in schizophrenia, however, relatively little is known about their precise nature and course. We do know that the emergence of depressive symptoms in individuals with schizophrenia has been associated with poor outcome, increased medication usage, greater morbidity at discharge, increased hospital readmission rates, and early relapse (Glazer et al., 1981; Herz, 1985; Roy et al., 1986; Ram et al., 1995). In addition, comorbid depression may contribute to the disturbingly high rates of suicide among patients with schizophrenia: a 10% incidence of suicide in the ®rst 10 years of illness and a 15% lifetime incidence have been reported (Miles, 1977; Roy, 1990), and suicide is considered as the main cause of premature death in this population (Roy et al., 1983; Sartorius et al., 1987; Allebeck, 1989; Caldwell and Gottesman, 1990). Depression, and especially the associated symptom of self-reported or perceived hopelessness, is an important comorbidity factor in the assessment of suicide risk (Caldwell and Gottesman, 1990). Depressive symptoms are common throughout the various phases of schizophrenia. However, differential diagnosis is hampered by dif®culties associated with distinguishing between such symptomatology and certain features of schizophrenia (particularly negative symptoms) or effects of its treatment (principally akinesia) and also by the dif®culty of recognizing depression in the presence of ¯orid psychosis (Siris, 2000). The Calgary Depression Scale (CDS) was developed for the purpose of identifying depression speci®cally in schizophrenia (Addington et al., 1990). However, most of the existing literature is still based on less speci®c assessment measures, and it is unclear how much the CDS, or other scales for that matter, are used in routine clinical practice. The majority of reported controlled studies of antidepressants in the treatment of depression in schizophrenia have employed adjunctive tricyclic antidepressants (TCAs). This approach has demon-
strated some ef®cacy, particularly in outpatients who are not acutely or actively psychotic (Plasky, 1991; Siris, 1991, 1994, 1995; Siris et al., 2000). Although few data are available regarding continuation and maintenance treatment with adjunctive antidepressants, one report provided strong evidence of the value of maintenance treatment in patients with postpsychotic depression that responded favorably to initial adjunctive antidepressant therapy (Siris et al., 1994). However, the combination of TCAs and many conventional antipsychotics raises pharmacokinetic and pharmacodynamic concerns (Gram and Overo, 1974; Loga et al., 1981; Linnoila et al., 1982; Cook et al., 1986). The International Survey of Depression in Schizophrenia was therefore designed to assess how these considerations and others, regarding the recognition and management of depressive symptoms in patients with schizophrenia, are being handled by psychiatrists in contemporary practice, and what further light this might shed on the understanding and treatment of this condition. 2. Methods A mail survey approach was adopted in order to survey the widest possible clinician base [a review of the problems of designing such questionnaires and evaluating the responses is provided in Hall et al. (1982)]. The International Survey of Depression questionnaires were distributed in March/April 1997 to approximately 80 000 psychiatrists in 24 countries world-wide, including 37 513 in the USA The list employed for identifying US psychiatrists was supplied by a specialist mailing house (Walsh, UK). Due to the extensive size and coverage of the survey, follow-up of non-responders was not possible. The questionnaire comprised 48 questions in the form of: Fixed-response questions addressing: ² Demographics of the respondents ² Symptoms relevant to the diagnosis of depression in schizophrenia ² Evaluation measures Ð which used and how routinely?
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² Factors that prompt the prescription of antidepressant medication ² Treatment selection ² Treatment practice, duration and dose
Table 2 Nature of respondents' current practice
Questions stimulated by case scenarios:
Hospital Clinic-/of®ce-based Private State-run health service University-af®liated Managed care organization Veterans' affair
² Diagnosis in response to case parameters ² Initial management plan (selection of new treatments, modi®cation of current treatments, psychosocial measures) ² Response to a development in the scenario, e.g. emergence of treatment-resistant symptoms or suicidal ideation. 2.1. Data handling Data were double-entered and centrally checked for consistency and reliability. All data analysis was carried out using Questionnaire Processing System (QPS) software (MRS Ltd, Wallington, Oxford, UK). This paper focuses primarily on the responses of psychiatrists in the USA, although comparisons are made with the ®ndings in other regions. Papers including more detailed discussions of the results in Europe and among the international respondent database are currently in preparation.
USA (%)
All regions (%)
47 50 40 15 26 7 10
61 39 36 24 23 6 4
Canada, 7.9%; and Europe, 4.9%. In total, 3443 questionnaires were returned, representing a response rate of 4.3%. The geographic spread and demographic pro®le of respondents are shown in Table 1. Data presented in Table 2 demonstrate the broad spectrum of respondents' practice at the time of the survey. Fifty-eight per cent of US psychiatrists indicated that outpatients accounted for more than 50% of their main practice Ð a somewhat higher ®gure than the average of 46% for respondents from all regions. This discrepancy was consistent with the fact that respondents world-wide reported responsibility for an average of 128 outpatients, compared with an average of 147 outpatients assigned to each clinician in the USA.
3. Results
3.1. Reported prevalence of depression
Altogether, 1128 US psychiatrists responded to the survey, a 3.0% response rate. Response rates in the three other geographic regions were: Australia, 9.6%;
The US respondents reported recognizing symptoms of signi®cant depression in a mean of 33% of ®rst-admission patients with psychotic symptoms,
Table 1 Demographics of respondents to survey
Total replies (percentage of total) Composition of respondent population [male/female (%)] Date of graduation from medical school (%) Pre-1960 1960±1969 1970±1979 1980±1989 Post-1990 Not stated Proportion of schizophrenia patients in respondents' current practice (%)
USA
All regions
1128 (38) 76/23
3443 (100) 76/23
15 20 21 27 11 7 31
9 14 27 35 9 6 31
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38% of patients in acute relapse, and 29% of patients with chronic stable schizophrenia. These ®gures are similar to those reported by psychiatrists world-wide: 29, 34 and 28%, respectively. Depression was most commonly encountered during the later stages of schizophrenia, particularly as acute psychotic symptoms resolved (see Fig. 1). Observations among clinicians in the USA differed somewhat from those among respondents world-wide with respect to the nature of depression in schizophrenic patients. As shown in Fig. 2, 57% of US psychiatrists identi®ed depression associated with substance use/abuse as the type that encountered they most frequently, compared with a signi®cantly lower ®gure of 35% of psychiatrists world-wide. Regarding effects on personal or vocational functioning, 77% of US respondents expressed a belief that depression signi®cantly added to the morbidity burden experienced by their schizophrenic patients, while 68% regarded its impact on the patient's family as signi®cant or highly signi®cant. These ®gures are of a similar order to those indicated by psychiatrists world-wide (68 and 60%, respectively). However, US respondents claimed a higher incidence of depression among
the caretakers of patients with schizophrenia: 43%, compared with 36% reported by the overall responders sample. 3.2. Treatment approaches 3.2.1. Antipsychotic therapy When considering treatment selection, 43% of US psychiatrists indicated that their choice of antipsychotic therapy for ®rst-admission patients was often or always in¯uenced by the appearance of concurrent depressive symptoms. Similar ®gures also reported that such comorbidity often or always in¯uenced their selection of treatment for relapse patients (46%) and for those with stable schizophrenic illness (42%). Participants were subsequently asked to indicate their ®rst choice of antipsychotic in three different clinical situations (Fig. 3). This revealed signi®cant differences in prescribing practice, particularly on ®rst admission, as follows: 1. At ®rst admission of a patient with ¯orid psychotic symptoms and features of depression. Conventional antipsychotic agents were indicated as the
Fig. 1. Time course of depression in schizophrenia.
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Fig. 2. Nature of depression in schizophrenia.
®rst-choice approach by 45% of US respondents, while 50% preferred an atypical agent (5% did not indicate a preference). These ®ndings are in contrast to those among respondents world-wide,
who indicated a higher preference for conventional (61%) than for atypical (34%) products. 2. Acute relapse in a patient with a known diagnosis of schizophrenia or schizoaffective disorder
Fig. 3. First choice of antipsychotic agent in speci®ed situations. Key: empty box: conventional antipsychotic; gray box: clozapine; black box: other atypical antipsychotic.
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presenting with the return of predominantly positive symptoms plus features of depression. In this situation, 38% of US respondents opted for a conventional antipsychotic agent as their treatment of choice, compared with 55% with a preference for atypical alternatives (7% were non-speci®c or did not indicate a preference). Corresponding ®gures for the entire world-wide respondent database were 52 and 41%, respectively. 3. A patient with schizophrenia or schizoaffective disorder with predominantly negative symptoms. Nine per cent of US respondents selected a conventional antipsychotic agent (no speci®c agent identi®ed) as their ®rst choice for such a patient, 8% speci®ed clozapine, and 78% indicated a preference for an atypical agent (5% were non-speci®c or did not indicate a preference). Again, these statistics indicated a lower use of conventional antipsychotics than among psychiatrists worldwide (20%), and a higher use of atypical agents (76% world-wide). Grouping conventional antipsychotic medications on the basis of high, medium or low potency, medium- or low-potency agents emerged as the treatment of choice of 9, 10, and 4% of US respondents in each of the three above clinical situations, respectively. However, the selection of these types of agent by psychiatrists world-wide was somewhat higher at 18, 19 and 9%, respectively. 3.2.2. Antidepressant therapy US respondents reported adjunctive prescription of antidepressant plus antipsychotic medication to 38% of their inpatients with schizophrenia and 43% of outpatients. Prescription of antidepressants was more common among US respondents than among psychiatrists world-wide, for both inpatients and outpatients. Table 3 summarizes the factors and symptoms most likely to prompt the prescription of an antidepressant to patients with recent-onset depressive symptomatology. Psychiatrists in the USA and world-wide identi®ed the same three symptoms as being the most in¯uential; however, US respondents tended to place more emphasis on insomnia and tearfulness, whereas respondents world-wide attached a greater signi®cance to diurnal mood variation and guilt.
Several antidepressants were frequently prescribed by both US psychiatrists and psychiatrists in all regions, most notably ¯uoxetine (62 and 49%, respectively), sertraline (62 and 43%, respectively) and paroxetine (49 and 45%, respectively). However, wider variations were seen in the usage of other, less popular, agents. Treatments of choice selected by more than 10% of US respondents were: trazodone (18%), nortriptyline (18%), buproprion (16%), and venlafaxine (15%), while those identi®ed by more than 10% of psychiatrists from all regions were: amitriptyline (21%), ¯uvoxamine (15%), clomipramine (14%), venlafaxine (13%), imipramine (11%), and trazodone (11%). US respondents considered adjunctive use of an antidepressant with an antipsychotic agent to be of clinical bene®t in 53% of schizophrenic patients with comorbid depression. The corresponding ®gure for psychiatrists world-wide was 48%. Figures were also similar with respect to the belief that antidepressant therapy would be appropriate for patients with stable residual disease and predominantly depressive symptoms, even in the absence of concomitant antipsychotic therapy: 49% of US psychiatrists and 51% of respondents world-wide. Adjunctive antidepressant therapy was rarely or never prescribed for patients with schizophrenia by 28% of US respondents, compared with 33% of psychiatrists world-wide. The most frequently cited reasons (indicated by 25% or more of US psychiatrists who rarely/never prescribed) for this avoidance of adjunctive therapy are shown in Table 4. 3.2.3. Drug combinations and treatment duration Twenty-two per cent of US respondents indicated a preferred combination of antipsychotic and antidepressant, the most popular combination being that of an atypical antipsychotic agent and a selective serotonin reuptake inhibitor (SSRI) (selected by 48% of those with any preferences). This combination was also the most popular among respondents world-wide, being indicated by 30% of psychiatrists in all regions. Thirty-one per cent of US respondents named drug combinations that they would avoid (respondents were allowed to name more than one combination), with thioridazine (cited by 29% of those who
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Table 3 Factors and symptoms most likely to prompt conjunctive antidepressant therapy from US psychiatrists in schizophrenia patients with recentonset depression Factor (relative importance a)
Symptom (% b)
Family history of depressive disorder (4.37) History of frequent recurrent admissions (3.78) Recent loss or rejection (3.76) History of substance abuse (3.31) High level of stress in family/household (3.24) Unmarried/divorced (3.13) Living alone (3.10) History of poor compliance (3.04) Unemployment (2.94) First admission (2.90) Supervised living arrangements (2.89) High educational level (2.82) Good interpersonal and social skills (2.82) Poor interpersonal and social skills (2.82) Chronic schizophrenia (2.81) Male gender (2.48) Low educational level (2.47) Female gender (2.42) Family of high social class (2.40) Low stress levels in family/household (2.39) Family of low social class (2.32)
Suicidal ideation (72) Hopelessness (50) Low mood (48) Insomnia (37) Anhedonia (32) Tearfulness (32) Early morning wakening (31) Guilt (26) Diurnal mood variation (25) Weight loss (23) Loss of appetite (21) Psychomotor retardation (18) Loss of energy (16) Withdrawal (15) Self-deprecation (15) Poor concentration (8) Somatic symptoms (7) Hypersomnia (7) Psychomotor agitation (3) Paranoia (2)
a b
Mean value measured on a scale of 1±5, where 1 unimportant, and 5 very important. Percentage of psychiatrists identifying a symptom as being likely to prompt the prescription of antidepressants.
identi®ed combinations to avoid) and clozapine (19%) emerging as the most commonly cited antipsychotics in this context. The most commonly avoided antidepressants in any combinations were the TCAs (indicated by 67% of those who expressed a preference) and monoamine oxidase inhibitors (MAOIs, avoided by 14.5% of those who named combinations to avoid). Respondents world-wide reported avoiding combinations including thioridazine at a rate of 18%, those including clozapine at a rate of 17%, and combinations with TCAs and MAOIs at rates of 52 and 21%, respectively. Forty-four per cent of US respondents indicated that antidepressant therapy would take 2±4 weeks to produce clinical bene®ts when added to an antipsychotic agent, while 30% indicated that a period of 4±6 weeks would be required. A large proportion of these psychiatrists (39%) felt that treatment, once initiated, should continue for 6± 12 months if the patient showed a satisfactory response.
3.2.4. Electroconvulsive therapy Thirty-six per cent of US psychiatrists reported using electroconvulsive therapy (ECT) to treat patients with schizophrenia or schizoaffective disorder with depressive symptoms. This ®gure is somewhat lower than the reported world-wide usage of 42%. 3.3. Psychotherapy The use of psychotherapeutic approaches was generally higher than average among US respondents. Table 4 Reasons most frequently cited by US psychiatrists for rarely/never prescribing conjunctive antidepressant plus antipsychotic therapies X Risk of exacerbation of psychotic disorder X Depression considered to be part of the psychotic disorder and responsive to antipsychotic medication X Risk of drug interactions X Risk of unfavorable side-effects X Depression considered to be due to psychosocial factors and responsive to psychosocial strategies
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Fig. 4. Frequently used psychotherapeutic approaches.
Psychoeducation emerged as the most popular technique, with 76% of US respondents indicating frequent use of this approach, compared with 58% of respondents world-wide. Fig. 4 illustrates the proportion of US respondents who indicated frequent use of various psychotherapeutic approaches. 3.3.1. Case scenarios Participants were asked to indicate their ®rst- and second-line therapeutic strategies in three separate case scenarios: Case 1. A patient with schizophrenia, previously well controlled with conventional antipsychotics, presenting with signi®cant depressive symptoms in the presence of a relapse of acute psychotic symptoms. Case 2. A patient presenting with an acute relapse manifesting as ¯orid psychotic symptoms promptly remitting on usual antipsychotic medication, but in whom depressive symptoms emerge during the second week. Case 3. A previously well-controlled patient with schizophrenia presenting with recent-onset depressive symptoms in the absence of any change in positive or negative symptoms or parkinsonism
(assuming that the patient is compliant and that there is no substance abuse, medical disorder or psychosocial precipitant to the admission). The diversity of preferred treatment approaches to these case scenarios was broad, particularly with respect to the acute-relapse case (case 1). The most popular ®rst-line therapeutic approaches to this case among US psychiatrists (respondents were allowed to select more than one ®rst-line strategy) were: increasing the dose of antipsychotic agent (64%) (56% world-wide); adding an antidepressant (62%) (58% world-wide); increasing psychosocial support and observing (44%) (44% world-wide); and switching to an alternative atypical antipsychotic agent (31%) (26% world-wide). Second-line strategies varied widely, but the most popular response was to add an antidepressant (cited by 42% of US respondents, compared with 40% world-wide). Although variable, the most popular US and world-wide ®rst- and second-line treatment strategies in cases 2 and 3 (again, selection of more than one strategy was permitted) involved adding an antidepressant and/or increasing psychosocial support and observing the patient. The use of antidepressant therapy as a ®rst-line strategy was indicated by 62%
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of US respondents for case 1 (acute relapse), 64% for case 2 (rapidly emerging postpsychotic depression) and 80% for case 3 (chronic stable schizophrenia with emerging depression). These ®gures are higher than those indicated by respondents world-wide (58, 54, and 73%, respectively). 3.3.2. Diagnosis and assessment of depressive symptoms In order to gain an insight into routine patient diagnosis and assessment practices, participants were asked a series of questions regarding their use of speci®c interview systems, assessment instruments, and depression rating scales. Routine clinical practice use of speci®c interview systems for the diagnosis of schizophrenia was relatively low among US respondents (17%), with the vast majority (79%) of those who applied such instruments using the structural clinical interview for DSM-III-R (SCID). Sixteen per cent of respondents world-wide used speci®c interview systems, with 83% of these favoring the SCID. Twenty-three per cent of both US and world-wide respondents reported routine use of standard instruments to assess patients with psychosis. Systems most frequently employed in the USA (respondents were asked to indicate all instruments routinely used) were: the Abnormal Involuntary Movement Scale (AIMS) (employed by 60% of those US respondents who used instruments); Brief Psychiatric Rating Scale (BPRS) (56%); Hamilton Depression Rating Scale (HDS) (40%); Beck Depression Inventory (BDI) (39%); and the Positive and Negative Syndrome Scale (PANSS) (37%). Geographical variations were evident in the levels of usage of these instruments, most notable with respect to the AIMS, which was reported to be routinely used by 60% of US psychiatrists but only 30% of respondents worldwide. Twenty-®ve per cent of US respondents claimed routine use of depression rating scales as part of the clinical assessment of patients with schizophrenia admitted with a clear depressive component to their presentation. The most commonly cited methods were the BDI (52%), HDS (49%), and BPRS (29%). Only 7 and 1% of US psychiatrists reported Ê sberg Depression routine use of the Montgomery±A Rating Scale (MADRS) and the CDS, respectively.
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Worldwide, the same percentage (25%) of psychiatrists claimed routine use of depression rating scales in patients with schizophrenia with comorbid depressive symptomatology. The methods cited were as follows: HDS, 57%; BDI, 42%; BPRS, 23%; PANSS, 23%; MADRS, 19%; AIMS, 12%; and the Scale for the Assessment of Negative Symptoms (SANS), 10%. 3.3.3. Suicide Psychiatrists in the USA reported the lowest national suicide rates among patients with schizophrenia: only 14% reported one patient suicide or more in the year prior to the survey, although 15% of US psychiatrists failed to respond to this question. Depression was identi®ed as a signi®cant factor in the majority of suicide cases. Twenty-three per cent of respondents world-wide reported one suicide or more among their schizophrenia patients in the year leading up to the survey, while 16% failed to register a response. 4. Discussion The questionnaire response rate among US psychiatrists was relatively low (3.0%) and, due to the nature of the study, follow-up of non-responders was not possible. Nevertheless, a database of responses from 1128 psychiatrists in the USA is a considerable sample size. How representative these data are of the total population of all practising psychiatrists could be questioned, as respondents were likely to be those with an active interest in the area under consideration. The demographics of the sample do, however, appear to represent a reasonable cross-section of clinical practice. While the possible in¯uence of existing literature, educational experiences, and commercial marketing campaigns cannot be discounted, one of the values of the International Survey was the likelihood that opinions expressed by the respondents would re¯ect their personal `in the ®eld' experience, at least to a substantial degree. In addition, responses to stimulus material in the form of case scenarios paralleled the responses to earlier questions relating to diagnosis and treatment. In general, selected treatment options also correlated with responses to questions regarding
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prescription frequency, indicating internal consistency of responses. 4.1. Prevalence of depression Although the data from this survey must be viewed in the context of the limitations of the questionnaire approach by which they were obtained, they nevertheless broadly corroborate the data from previous prevalence surveys and indicate recognition of a substantial clinical burden of depressive symptomatology in schizophrenia (McGlashan and Carpenter, 1976). US clinicians reported encountering depressive symptoms in about one-third of their schizophrenic patients, and three-quarters demonstrated a good appreciation of the magnitude of the associated additional burden imposed on patients and their caretakers. The general agreement, with respect to the prevalence, course, and nature of depressive symptoms in patients with schizophrenia, observed internationally is noteworthy, since this establishes the scale of the problem and the recognized need to address it. The survey ®ndings point to a relatively high level of awareness among US psychiatrists of the impact of comorbid depression on patients with schizophrenia and their families, but it is unclear whether this re¯ects a more problematic course of depression in schizophrenia in the USA or simply demonstrates a greater sensitivity to the problem among this particular professional group. 4.2. Depression rating scales Approximately one-fourth of US respondents reported the routine use of depression-rating scales. For the most part, they utilized older depression rating scales that are not speci®c to schizophrenia (mainly the BDI and HDS). Only about 1% utilized the CDS, a relatively simple scale that is designed to differentiate depression from negative symptoms and extrapyramidal symptoms in subjects with schizophrenia (Addington et al., 1993, 1994). Interestingly, however, when psychiatrists were asked to identify the symptoms that most in¯uence their decision to prescribe an antidepressant, ®ve of the most commonly cited factors (suicidal ideation, hopelessness, low mood, diurnal mood, morning wakening) were among the eight speci®c items of the CDS.
4.3. Managing depression in schizophrenia Regarding the overall choice of antipsychotic agents, the majority of US respondents indicated that an atypical agent would be their ®rst-choice therapy in all three clinical situations presented. Conventional antipsychotics remained the treatment of choice for a large proportion of respondents, particularly for a ®rst-admission case, but, in comparison with the world-wide ®ndings, their popularity among US clinicians was limited. This ®nding is indicative of a move toward a wider prescription of atypical agents where readily available. The use of atypical antipsychotics may be stimulated, at least in part, by their reported superiority to standard neuroleptics in terms of the treatment of depressive symptoms in schizophrenia (Azorin, 1995; MoÈller et al., 1995; Tandon et al., 1997; Tollefson et al., 1997, 1998; Keck et al., 1998; Siris, 2000). Novelty and marketing efforts may be further factors in their popularity. US psychiatrists showed a relatively high tendency to treat depression directly in patients with schizophrenia. Bearing in mind the lower reported suicide rates in this region, it would seem reasonable to suggest that greater recognition of the importance of such comorbidity contributes to improved outcomes. Differences in clinical practice approaches to in- and outpatient populations might have been expected, as existing research literature indicates that adjunctive antidepressant use can be effective in schizophrenic outpatients with depression but does not support this approach in inpatient populations (Siris, 1995). However, the present study failed to reveal any such differences, suggesting that psychiatrists apply their judgement of best practice concerning the use of adjunctive antidepressants across all patients with schizophrenia with comorbid depressive symptoms, regardless of the setting. Notably, this pattern of practice seems to be at variance with the controlled observations that the addition of an antidepressant to the antipsychotic treatment of patients with acute psychotic schizophrenia or schizoaffective disorder may actually retard the antipsychotic response (Kramer et al., 1989). Clinical practice guidelines published by the American Psychiatric Association (1997) recommend that depressive symptoms occurring comorbidly with acute psychotic symptoms should only be treated
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after the psychoses have been treated with antipsychotic medications (MoÈller et al., 1995). These guidelines urge caution in the adjunctive use of antidepressants during the acute phase of the illness and alert psychiatrists to the possibility of an exacerbation of psychotic symptoms. Approximately half of the US respondents to the survey indicated that they would consider antidepressant use even in the absence of concomitant antipsychotic therapy Ð a result that is surprising since this represents an approach that is not supported by the bulk of the literature in this area (Siris et al., 1978; Siris, 1995, 2000; American Psychiatric Association, 1997). The responses to questions regarding treatment approaches and case scenarios demonstrated a considerable variation in treatment strategies, particularly on ®rst admission and regarding second-line approaches. It seemed likely that clinicians' own perceptions of the underlying cause of the depressive component formed the basis of the selected treatment approach. Regardless of this variability, prescription of an antidepressant was indicated by the majority of US respondents in all three case scenarios, particularly for depressive symptoms arising in patients with chronic stable schizophrenia. The approach advocated by the American Psychiatric Association is to prescribe antidepressant medication for depressive symptomatology that persists beyond, or emerges after, the remission of acute psychosis in patients with schizophrenia (American Psychiatric Association, 1997). In general, treatment is indicated where depressive symptoms satisfy the syndromal criteria for major depressive disorder or are suf®ciently severe to cause notable distress or interfere with patient functioning. In their responses to this survey, US psychiatrists appear to indicate that they are sometimes willing to treat symptoms of depression as well as the depressive syndrome with antidepressive agents and thereby go beyond the therapeutic indication supported in the research literature. They also go beyond the research literature when they indicate a willingness to use antidepressant medications as adjunct antipsychotic agents in schizophrenic patients who continue to manifest substantial psychotic symptomatology. This might retard antipsychotic ef®cacy, and more psychiatrist education may be required. Alternatively, favorable clinical experience may be guiding these psychia-
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trists, and more research may be indicated to see where this is the case. Similarly, most studies of antidepressants in this context have employed TCAs (Siris, 1991, 2000). This survey indicates that many psychiatrists appear to feel comfortable utilizing other classes of antidepressants or report a speci®c preference for an atypical antipsychotic combined with an SSRI. This may indicate another area where future controlled clinical trials may be valuably informative. However, perhaps dissuaded by concerns regarding the safety of combinations of TCAs with many conventional antipsychotic agents (Loga et al., 1981; Linnoila et al., 1982), more than a quarter of US participants in the survey reported rarely or never prescribing adjunctive antidepressant medications. They may have had different clinical experiences that now guide their practice and should be learned about, or, alternatively, they may bene®t from education concerning the potential bene®ts of adjunctive antidepressant medications in appropriately selected schizophrenic patients. 5. Conclusion The ®ndings of the International Survey of Depression in Schizophrenia suggest that a majority of US psychiatrists are highly aware of the impact and associated problems of depression in schizophrenia and actively use adjunctive antidepressant medications in its treatment. There remain, however, a signi®cant minority who perceive less of a depression burden in schizophrenia and rarely, if ever, utilize combination treatment with an antidepressant. Some of the most frequently employed adjunctive antidepressant treatments have yet to be fully evaluated in controlled trials, and it appears that their popularity is largely derived from ongoing anecdotal clinical experience. Further scienti®c guidance in this area is obviously required, and large-scale surveys of the kind reported here may provide a useful stimulus and help frame questions for this endeavor most fruitfully. Acknowledgements This survey was supported by an unrestricted
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educational grant from P®zer Pharmaceuticals Group, New York, USA. This work was presented, in part, at the 37th Annual Meeting of the American College of Neuropsychopharmacology, Las Croabas, Puerto Rico, on December 14, 1998, and at the 7th International Congress on Schizophrenia Research, Santa Fe, New Mexico, on April 17, 1999.
References Addington, D., Addington, J., Schissel, B., 1990. A depression rating scale for schizophrenics. Schizophr. Res. 3, 247±251. Addington, D., Addington, J., Maticka-Tyndale, E., 1993. Assessing depression in schizophrenia: The Calgary Depression Scale. Br. J. Psychiatry 163, 39±44. Addington, D., Addington, J., Maticka-Tyndale, E., 1994. Speci®city of the Calgary Depression Scale for schizophrenia. Schizophr. Res. 11, 239±244. Allebeck, P., 1989. Schizophrenia, a life-shorting disease. Schizophr. Bull. 15, 81±89. American Psychiatric Association, 1997. Practice guidelines for the treatment of patients with schizophrenia. Am. J. Psychiatry 154 (Suppl.), 1±63. Azorin, J.M., 1995. Long-term treatment of mood disorders in schizophrenia. Acta. Psychiatr. Scand. 91 (Suppl. 388), 20±23. Caldwell, C.B., Gottesman, I.I., 1990. Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophr. Bull. 16, 571±589. Cook, P.E., Dermer, S.W., Cardamone, J., 1986. Imipramine± ¯upenthixol decanoate interaction. Can. J. Psychiatry 31, 235±237. Glazer, W., Prusoff, B., John, K., Williams, D., 1981. Depression and social adjustment among chronic schizophrenic outpatients. J. Nerv. Ment. Dis. 169, 712±717. Gram, L.F., Overo, K.F., 1974. In¯uence of neuroleptics and benzodiazepines on metabolism of tricyclic antidepressants in man. Am. J. Psychiatry 131, 863±866. Hall, W., Weekes, P., Harvey, R., Andrews, G., 1982. A survey of practising psychiatrists' views on the treatment of agoraphobia. Aust. N. Z. J. Psychiatry 16, 225±233. Herz, M., 1985. Prodromal symptoms and prevention of relapse in schizophrenia. J. Clin. Psychiatry 46, 22±25. Keck, P., Buffenstein, A., Ferguson, J., Feighner, J., Jaffe, W., Harrigan, E.P., Morrissey, M.R., 1998. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 140, 173±184. Kramer, M.S., Vogel, W.H., DiJohnson, D., Dewey, D.A., Sheves, P., Gavicchia, S., Little, P., Schmidt, R., Kimes, I., 1989. Antidepressants in `depressed' schizophrenic inpatients: a controlled trial. Arch. Gen. Psychiatry 46, 922±928. Leff, J., 1990. Depressive symptoms in the course of schizophrenia.
In: DeLisi, L.E. (Ed.). Depression in Schizophrenia. American Psychiatric Press, Washington, DC, pp. 3±23. Linnoila, M., George, L., Guthrie, S., 1982. Interaction between antidepressants and perphenazine in psychiatric patients. Am. J. Psychiatry 139, 1329±1331. Loga, S., Curry, S., Lader, M., 1981. Interactions of chlorpromazine and nortriptyline in patients with schizophrenia. Clin. Pharmacokinet. 6, 454±462. McGlashan, T.H., Carpenter, W.T., 1976. Postpsychotic depression in schizophrenia. Arch. Gen. Psychiatry 33, 231±239. Miles, C.P., 1977. Conditions predisposing to suicide: a review. J. Nerv. Ment. Dis. 164, 231±264. MoÈller, H.-J., MuÈller, H., Borison, R., Schooler, N.R., Chouinard, G., 1995. A path analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients: a re-evaluation of the North American risperidone study. Eur. Arch. Psychiatry Clin. Neurosci. 245, 45±49. Plasky, P., 1991. Antidepressant usage in schizophrenia. Schizophr. Bull. 17, 649±657. Ram, R., Jandorf, L., Dixon, L., Bromet, E., 1995. Depressive syndromes in ®rst admission patients with schizophrenic disorders: the extent, phenomenology, correlates and change over six months. Schizophr. Res. 15, 1±2. Roy, A., 1990. Relationship between depression and suicidal behaviour in schizophrenia. In: DeLisi, L.E. (Ed.). Depression in Schizophrenia. American Psychiatric Press, Washington, DC, pp. 41±58. Roy, A., Thompson, R., Kennedy, S., 1983. Depression in chronic schizophrenia. Br. J. Psychiatry 142, 465±470. Roy, A., Schreiber, J., Mazonson, A., Picker, D., 1986. Suicidal behaviour in chronic schizophrenia: A follow up study. Can. J. Psychiatry 31, 737±740. Sartorius, N., Jablensky, A., Ernberg, G., et al., 1987. Course of schizophrenia in different countries: some results of a WHO international comparative 5-year follow-up study. In: Hafner, H., et al. (Eds.). Search for the Causes of Schizophrenia. Springer, Berlin, pp. 107±113. Siris, S.G., 1991. Diagnosis of secondary depression in schizophrenia: implications for DSM-IV. Schizophr. Bull. 17, 75±98. Siris, S.G., van Kammen, D.P., Docherty, J.P., 1978. The use of antidepressant edication in schizophrenia. Arch. Gen. Psychiatry 35, 1368±1377. Siris, S.G., 1994. Assessment and treatment of depression in schizophrenia. Psychiatr. Ann. 24, 463±467. Siris, S.G., Bermanzohn, P.C., Mason, S.E., Shuwall, M.A., 1994. Maintenance imipramine therapy for secondary depression in schizophrenia. Arch. Gen. Psychiatry 51, 109±114. Siris, S.G., 1995. Depression and schizophrenia. In: Hirsch, S.R., Weinberger, D. (Eds.). Schizophrenia. Blackwell Scienti®c, London, pp. 128±145. Siris, S.G., 2000. Depression in schizophrenia: perspective in the era of ªatypicalº antipsychotic agents. Am. J. Psychiatry 157, 1379±1389. Siris, S.G., Pollack, S., Bermanzohn, P., Stronger, R., 2000. Adjunctive imipramine for a broader group of post-psychotic depressions in schizophrenia. Schizophr. Res. 44, 187±192.
S.G. Siris et al. / Schizophrenia Research 47 (2001) 185±197 Tandon, R., Harrigan, E., Zorn, S.H., 1997. Ziprasidone: a novel antipsychotic with unique pharmacology and therapeutic potential. J. Serotonin Res. 4, 159±177. Tollefson, G.D., Beasley, C.M., Tran, P.V., Street, J.S., Krueger, J.A., Tamura, R.N., Graffeo, K.A., Thieme, M.E., 1997. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an
197
international collaborative trial. Am. J. Psychiatry 154, 457± 465. Tollefson, G.D., Sanger, T.M., Beasley, C.M., Tran, P.V., 1998. A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia. Biol. Psychiatry 43, 803±810.