Acta Psychiatr Scand 2002: 105: 189195 Printed in UK.

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ACTA PSYCHIATRICA SCANDINAVICA ISSN 0001-690X

Clinical issues related to depression in schizophrenia: an international survey of psychiatrists

Addington DD, Azorin JM, Falloon IRH, Gerlach J, Hirsch SR, Siris SG. Clinical issues related to depression in schizophrenia: an international survey of psychiatrists. Acta Psychiatr Scand 2002: 105: 189195. Munksgaard 2002. Objective: Depressive symptoms in schizophrenia are associated with a substantial morbidity and mortality burden. The `International Survey of Depression in Schizophrenia' was designed to evaluate current awareness and clinical approaches in this area. Method: A 48-item questionnaire was distributed to approximately 80 000 consultant psychiatrists world-wide. Responses were analysed using descriptive statistics. Results: Respondents demonstrated considerable awareness of the prevalence and consequences of depression in schizophrenia. Although there was widespread adjunctive use of antidepressants, one-third of respondents indicated that they rarely or never prescribe these agents in combination with antipsychotic medication. There were considerable variations in opinions about the best approach to the treatment of depressive symptoms associated with schizophrenia. Conclusion: The considerable clinical burden of depressive symptomatology in schizophrenia was acknowledged by the majority of respondents to this survey. There was, however, little agreement on the best management strategy.
Introduction

D. D. Addington1, J. M. Azorin2, I. R. H. Falloon3, J. Gerlach4, S. R. Hirsch5, S. G. Siris6

1 Foothills Hospital, Calgary, Alberta, Canada, 2CHU St Marguerite, Marseille, France, 3The University of Auckland, Auckland, New Zealand, 4St Hans Hospital, Roskilde, Denmark, 5Charing Cross and Westminster Medical School, London, UK and 6Albert Einstein College of Medicine, New York, USA

Key words: antidepressive agents; antipsychotic agents; depression; electroconvulsive therapy; patient care management; schizophrenia Donald Addington, Department of Psychiatry, Foothills Hospital, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada E-mail: addingto@ucalgary.ca Accepted for publication 5 September, 2001

Descriptive and epidemiological studies have documented a depression-like syndrome occurring during the longitudinal course of schizophrenia in approximately 25% of patients (1, 2). However, it is only relatively recently that attempts have been made towards understanding the nature and course of this syndrome. Nevertheless, the inclusion of post-psychotic depression as a diagnostic entity in ICD-10 and in the Appendix to DSM-IV indicates that it is being increasingly recognized. Depressive symptoms in patients with schizophrenia may have diverse aetiology: they may be part of the core pathology, or they may be reactive post-psychotic, pharmacogenic or akinetic (3). In a recent study, Bottlender and colleagues found depressive symptoms to be frequent among rst admitted patients with schizophrenia (4). Of around 1000 patients admitted, almost 40% had a depressed mood at the time of admission, while 15% fullled the criteria for clinically signicant

depression. Depressed schizophrenic patients were more likely to have suicidal tendencies, and had more family members with psychiatric disorders other than schizophrenia than the non-depressed. Several other studies have indicated that depressive symptoms are associated with increased use of medications, early relapse and increased hospital admission rates (58). Falloon identied depressive symptoms as the most common cause of re-admission among schizophrenia patients (9). In a 5-year follow-up of a cohort of 121 schizophrenia suerers (10) 50% experienced one or more episode of depression, many of which alone were suciently severe to warrant admission. With respect to treatment approaches, controlled studies of coprescribed tricyclic antidepressants (TCAs) have shown some ecacy (1, 11, 12), and there is evidence that adjunctive TCAs may be useful for the maintenance treatment of post-psychotic depression (13). However, there are currently no well-dened approaches to recognition and management of depressive symptoms associated with schizophrenia. 189

Addington et al. Consequently, the International Survey of Depression in Schizophrenia was undertaken to evaluate how psychiatrists recognize, assess and treat depressive symptoms in schizophrenia, and to examine perceptions of the additional burden imposed by comorbid depression.
Material and methods

survey have been published separately (15). This paper deals with results of the complete study, and compares and contrasts results obtained between dierent regions.
Results Demographics

In order to survey as wide a group as possible, a postal questionnaire was selected as the most practical approach. The issues involved in designing such questionnaires and evaluating the responses are described elsewhere (14). The survey was devised under the guidance of a group of specialists and was distributed in March/ April 1997 to approximately 80 000 consultant psychiatrists (identied via specialist mailing lists) in 24 countries world-wide. The questionnaire was prepared in ve languages: English, French, German, Italian and Spanish. Because of the extensive distribution and global coverage of the survey, follow-up of non-responders was not possible. The questionnaire consisted of 48 questions in the form of: Fixed-response questions addressing: Demographics of responders Symptoms relevant to the diagnosis of depression in schizophrenia Evaluation measures which ones used and how frequently Factors perceived as stimuli to the initiation of antidepressant therapy Treatment selection Treatment practice, duration and dose Questions stimulated by case scenarios: Diagnosis in response to case parameters Initial management plan (selection of new treatments, modication of current treatments, psychosocial measures) Response to a development in the scenario (for example, emergence of resistant symptoms or suicidal ideation).
Data handling

The demographics of respondents are shown in Table 1. In total, 3443 (4.3%) questionnaires were returned. Response rates (i.e. number of questionnaires returned as a percentage of those distributed) were above average in Australia (9.6%), Canada (7.9%) and Europe (4.9%), but somewhat lower than average in the USA (3.0%). There was a broad spread of disciplines and practice mix within the sample. European, Australian and Canadian clinicians were more likely to have hospital-based practices, whereas US respondents were more likely to be predominantly clinic- or oce-based. Out-patients were the major component (>50%) of almost half the respondents' practice (46%; Table 1). Fewer respondents reported a majority of in-patients, with 17% reporting a majority of short-stay and 8% longstay/residential in-patients (Table 2). European
Table 1. Demographics of sample and characteristics of respondents clinical practice Total number of replies Male/female (%) Graduation: pre/post-1980 (%) Nature of practice (% respondents)a Hospital Clinic/office-based Private State-run/national health service University-affiliated Other/unknown 3443 (4.3%) 76/24 50/44 61 39 36 24 23 6

Nature of patients comprising >50% of main practice (% respondents) Out-patient 46 Short-stay in-patient 17 Private clinic based 10 Long-stay/residential in-patient 8 Other <3 Patients with schizophrenia/schizoaffective disorder (%) 30.8 (SD 24.5)

As well as analysing the total sample, responses were also subgrouped under the following four regions: Australia, Canada, Europe and USA. All data analysis was carried out using Questionnaire Processing System (QPS) software (MRS Ltd, Wallington, Oxford, UK). In the USA, the questionnaire was distributed to 37 513 psychiatrists. Results of the US part of this 190

Schizophrenic/schizoaffective patients with significant depression (%) First-admission patients 29.2 (SD 20.5) Acute relapse patients 33.9 (SD 20.2) Stable patients 28.1 (SD 18.9) Nature of depression (relative frequency)b Secondary to chronic discouragement Integral to schizophrenic illness Associated with substance use or abuse Pharmacogenic (other than EPS-related) Akinetic (EPS-related)
a b

3.4 3.2 2.9 2.6 2.5

(SD 1.0) (SD 1.0) (SD 1.2) (SD 1.1) (SD 1.0)

Respondents were allowed to specify more than one practice type. Measured on a scale of 1 (least frequent) to 5 (most frequent).

Clinical issues related to depression in schizophrenia

Table 2. Patient diagnosis and evaluation Respondents who routinely use a specific interview system for the diagnosis of schizophrenia (%) Specific interview systems used (%)a Structural clinical interview for DSM-III-R (SCID) Other Respondents who routinely use assessment instruments to evaluate patients with psychoses (%) Specific assessment instruments used (%)b Brief Psychiatric Rating Scale (BPRS) Positive and Negative Symptom Scale (PANSS) Other Respondents who routinely use depression rating scales to Assess patients with schizophrenia/schizoaffective disorder With a clear depressive component (%) Specific depression rating scales used (%)c Hamilton Depression Rating Scale (HDRS) Beck Depression Inventory (BDI) Other
a

Treatment approaches: antipsychotic therapy

16

83 <9 23

51 45 46 25

57 42 23

Base All respondents who routinely use a specific interview system for the diagnosis of schizophrenia. b Base All respondents who routinely use assessment instruments. c Base All respondents who routinely use depression rating scales.

clinicians generally had a larger proportion of in-patient practice than respondents in the other three regions, and out-patients made up a larger proportion of the practice of US clinicians than of their counterparts in the other regions.
Depressive symptoms in patients with schizophrenia

Participants were asked to indicate their rst choice of antipsychotic in three dierent hypothetical clinical situations. Prescribing habits were seen to dier, particularly on rst admission. Table 3 shows the respondents' current treatment approaches. For both rst-admission and acute-relapse patients with positive and depressive symptoms, a conventional antipsychotic was the most commonly chosen agent. Of these, high potency agents were selected by approximately two-thirds of respondents. Atypical agents were chosen by approximately one-third of respondents. However, for patients with predominantly negative symptoms, over three-quarters of respondents indicated that they would choose an atypical antipsychotic agent. Among European psychiatrists, prescription of conventional antipsychotic agents was more common than average (67% on rst admission) and that of novel agents less common (21% on rst admission). US psychiatrists, on the other hand, reported high usage of a novel agent (50%) on rst admission and more limited administration of a conventional drug (44% on rst admission). This trend held true in all three hypothetical situations.
Treatment approaches: antidepressant therapy

Approximately one-third of respondents' patients had a diagnosis of schizophrenic/schizoaective disorder. Of these, approximately one-third had signicant depressive symptomatology. Rates were similar for rst admission, acute relapse and stable patients, and were consistent across geographical regions. Respondents perceived that depression was most frequently secondary to chronic discouragement (demoralization syndrome) or integral to the schizophrenic illness (see Table 1).
Diagnosis and assessment of depressive symptoms

The reported use of specic interview systems for the diagnosis of schizophrenia within routine clinical practice was low (16%). Of those who did use them, the majority opted for a structural clinical interview for DSM-III-R (SCID). Table 2 shows the patient diagnosis and evaluation systems. The Brief Psychiatric Rating Scale (BPRS) was the most commonly used psychosis rating instrument, and the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were the most frequently used depression rating scales. Overall, 62% of respondents reported never routinely using any interview systems or rating scales.

On average, respondents indicated prescribing an antidepressant in combination with antipsychotic medication in approximately one-third of either their in-patients or out-patients. The symptoms most likely to prompt the coprescription of an antidepressant are summarized in Table 3. Other factors were also considered important in inuencing the prescription of an antidepressant, such as family history of depressive disorder, recent loss or rejection and a history of frequent recurrent admissions. Overall, 33% of respondents reported rarely or never prescribing antidepressant plus antipsychotic combinations. The most frequently cited reasons for this are summarized in Table 3. The most common reason was the risk of exacerbating the psychotic disorder, although several other factors gured highly.
Drug combinations and treatment duration

Twenty-nine per cent of respondents identied their preferred antipsychotic plus antidepressant combinations. The most frequent combination was a novel antipsychotic agent and a selective 191

Addington et al.
Respondents first-choice antipsychotic treatment (%) (conventional antipsychotica/atypical antipsychotic)b First-admission patient with florid psychotic symptoms and features of depression 58/33 Acute-relapse patient with return of predominantly positive symptoms plus depression 49/38 Patient with predominantly negative symptoms 15/74 Symptoms most likely to prompt coprescription of an antidepressant with antipsychotic medication in a previously well-controlled schizophrenia patient presenting with recent-onset depression (% respondents)c Suicidal ideation 66 Low mood/hopelessness/tearfulness/anhedonia 57 Early morning wakening/insomnia 35 Morning depression 40 Guilt/paranoia 38 Other 21 Co-prescription of antidepressants with antipsychotic medications in patients with schizophrenia or schizoaffective disorder (%) In-patients 33.7 (SD = 20.8) Out-patients 36.6 (SD = 21.5) Reasons for rarely or never prescribing antidepressants in combination with antipsychotic medications (%)c Risk of exacerbating psychotic disorder 49 Consider depression part of a psychotic disorder and, therefore, responsive to antipsychotic 48 medication Consider depression to be the result of psychosocial factors and responsive to 31 psychosocial strategies Risk of drug interactions 28 Side-effects 23 Other 20 Respondents who used ECT to treat patients with schizophrenia/schizoaffective disorder with depressive symptoms (%)
a b

Table 3. Current approaches to the treatment of depression in schizophrenia

42

A single low, medium or high potency conventional antipsychotic. One of clozapine, risperidone, olanzapine, sertindole. c Respondents were allowed to select up to five options.

serotonin reuptake inhibitor (SSRI) (30% of respondents who expressed a preference). Thirtyone per cent of psychiatrists indicated that they would actively avoid certain drugs. The most commonly avoided antipsychotics were haloperidol (24%) and thioridazine (18%); the most commonly avoided antidepressants were amitriptyline (21%) and uoxetine (15%). In terms of the time taken for an antidepressant to begin to yield clinical benets when added to an antipsychotic, 46% of responding psychiatrists felt that a period of 24 weeks would be necessary, and 30% estimated that 46 weeks would be required. A large proportion of respondents (31%) thought that treatment should continue for 612 months if the patient responded satisfactorily.
Non-pharmacological treatment approaches

The use of psychotherapeutic approaches in the treatment of depression was generally lower in Europe than in other regions. Psychoeducation was the most commonly used approach, with 7378% respondents from the USA, Australia and Canada indicating frequent (50%) use of this approach, compared with only 42% of European respondents.
Case scenarios

Overall, 42% of respondents reported using electroconvulsive therapy (ECT) to treat patients with schizophrenia or schizoaective disorder. The survey revealed that ECT was rarely used as a rst-line strategy, was often used as a second-line strategy when one or two antidepressant drugs failed, and was predominantly used as a treatment when all other treatments failed.

Participants were asked to indicate their choice of rst- and second-line therapeutic strategy in three case scenarios, outlined in Table 4. The use of antidepressant therapy as a rst-line strategy was indicated by 58% of respondents to Case 1 (acute relapse), 54% to Case 2 (post-psychotic depression) and 73% to Case 3 (chronic stable schizophrenia). In addition to coprescribed antidepressants, there was a broad diversity of treatment approaches indicated in response to the various case scenarios. This was particularly true of therapy in the acute relapse case (Case 1). In the case of postpsychotic depression (Case 2), approximately onequarter of respondents indicated that their rst-line strategy would be to decrease the dose of agent.

192

Clinical issues related to depression in schizophrenia

Table 4. Case scenarios: strategies for first-/second-line approaches. Case 1: Acute relapse, a patient with schizophrenia, previously well-controlled with conventional antipsychotic medication, presents with significant depressive symptoms in the presence of a relapse of acute psychotic symptoms. Case 2: Post-psychotic, a patient with an acute relapse manifesting as florid psychotic symptoms promptly remits on unusual psychiatric medication, but depressive symptoms emerge in the second week. Case 3: Stable, a previously well-controlled patient with schizophrenia, presently with recent-onset depression symptoms in the absence of any change in positive or negative symptoms or Parkinsonism Strategy (% respondents)a Increase dose of antipsychotic agent Decrease dose of antipsychotic agent Switch to alternative conventional antipsychotic agent Switch to clozapine Switch to alternative atypical antipsychotic agent Add another CNS-active agentb,c Add an antidepressant Replace antipsychotic medication with an antidepressant Switch to alternative antidepressant medication Change the antidepressant dosage Apply ECT Increase psychosocial support Other
a

Respondents reported a high incidence of depression among carers of schizophrenia patients. They also perceived that depression constituted a considerable additional psychosocial burden for both schizophrenic patients and their carers; Table 5 provides more details on how this was rated.
Discussion

Case 1 56 7 10 9 26 10 58 1 <1 <1 <1 44 <1

Case 2 5 26 3 2 9 5 54 1 <1 <1 <1 43 1

Case 3 2 13 3 3 9 6 73 1 <1 <1 <1 37 <1

Respondents were allowed to select more than one strategy for each case scenario. b For example, antiseizure medication, anti-Parkinsonian agent, a benzodiazepine or lithium. c Maximum percentage for a single example.

The indicated use of psychosocial support was high in all three case scenarios.
Suicide

Although 61% of respondents had not encountered a suicide among their patients with schizophrenia in the past year (16% did not answer), 815 respondents reported at least one suicide. Depression was identied as a signicant factor in the majority of these cases, as shown in Table 5. Ten respondents reported 10 or more suicides among their schizophrenia patients in the previous year.
Table 5. Consequences of depression for patient/family Proportion of respondents reporting one or more suicide among schizophrenia/schizoaffective disorder patients in past year (%) Proportion of respondents reporting depression as a significant factor in one or more suicide (%)a Respondents estimated risk of completed suicide in a patients lifetime (%) 24

78 18.4 (SD 14.0)

Estimated additional psychological morbidity of depression in schizophreniab For patient 3.8 (SD 0.9) For patients family 3.7 (SD 0.9) Incidence of significant depression in carers of schizophrenia/schizoaffective disorder patients (%)
a b

36.4 (SD 20.3)

Base All respondents reporting one or more suicides. Additional morbidity estimated on a scale of 1 (minimum) to 5 (maximum).

The considerable clinical burden of depressive symptomatology in schizophrenia was acknowledged by the majority of respondents to this survey. Respondents demonstrated considerable awareness of the prevalence and consequences of depression in schizophrenia. However, there were considerable variations in opinions about the best approach to the treatment of depressive symptoms associated with schizophrenia. Although there may have been sampling error as a result of inaccuracies in mailing lists, the impact of any such error is not likely to have been signicant in this large sample size (3443). The overall response rate was relatively low, and the large scale of the survey did mean that follow-up of non-responders was not possible. Several factors may have contributed to the low response rate. There was no follow-up of nonrespondents. Studies suggest that a number of dierent follow-up reminder techniques can increase response rates (16). Other studies suggest that decreasing the amount of material increases the chance of completion (17). With 48 separate questions, the questionnaire may have been too long. Finally, non-response is also associated with a lack of activity or interest in the specic study area (18). It can probably be presumed that respondents were likely to be those with an active interest in this clinical area. Another question is that of whether the responses reected actual clinical practice on the part of the respondents. It is probable that the indicated treatment recommendations were based on personal experience. In addition, responses to stimulus material in the form of case scenarios paralleled the responses to earlier questions relating to diagnosis and treatment, and the selection of treatments generally correlated with responses to questions regarding the frequency of prescription. These ndings may indicate an internal consistency of responses. Although the data from this survey must be viewed in the context of the limitations of a questionnaire approach, they nevertheless corroborate the data from previous prevalence studies and indicate a substantial clinical burden of depressive symptomatology in schizophrenia (19, 20). 193

Addington et al. The responses indicated that, in approximately one-third of patients, clinicians recognized depressive symptoms as a key factor requiring therapeutic intervention. General agreement was seen in all geographical regions surveyed, with respect to the prevalence, course and nature of depressive symptoms in patients with schizophrenia, thus establishing the scale of the problem and the recognized need to address it. However, there was little agreement among respondents on the best strategy for managing depression in schizophrenia, particularly concerning acute relapse patients. Therefore, it seems that therapeutic approaches are likely to be based on each clinician's own perceptions of the underlying cause of the depressive component. Overall, the majority of respondents (58%) indicated use of a conventional antipsychotic agent for rst-admission patients and only 33% reported that they would use an atypical agent. However, 50% of psychiatrists in the USA (where atypical agents are readily available) cited novel antipsychotic agents as their therapy of choice for this patient group. This could be indicative of a move towards novel agents where they are available. However, there is still high-level prescribing of high-potency, conventional antipsychotic drugs, especially on rst admission. There was a considerable variation in treatment approaches. In a patient who has depressive symptoms and is experiencing a relapse of acute psychotic symptoms, addition of an antidepressant (58%) or use of increased doses of antipsychotic agents (56%) were indicated with a similar frequency, and 26% of respondents indicated that they would switch to another novel antipsychotic. In the event of post-psychotic depression immediately following an episode of psychosis, a large proportion of psychiatrists (54%) would add an antidepressant, and approximately one-quarter would decrease the dose of antipsychotic, thus suggesting a belief that depressive symptoms are related to the eects of drug therapy. There was more consistency in respondents' approaches to depression occurring in chronic stable schizophrenia, with the majority (73%) indicating that antidepressant therapy would constitute at least part of their rst-line strategy. This is consistent with reported studies of coprescribed antidepressants that indicate ecacy particularly in outpatients who are not acutely or actively psychotic (1, 2, 1113). However, one-third of respondents indicated rarely or never coprescribing antidepressant therapy. Fears of exacerbating the psychotic disorder, risk of drug interactions and concerns regarding 194 side-eects were the major reasons for respondents avoiding coprescription of antidepressants. It is known that, although clinically eective, the combination of TCAs with many conventional antipsychotic agents can give rise to safety concerns (21, 22). In recognition of the potential for exacerbation of psychotic symptoms, the American Psychiatric Association has published a clinical practice guideline urging caution in the coprescription of antidepressant medications during the acute phase of schizophrenia (23). In general, it is recommended that such coprescribed treatment should be delayed until the psychosis has been treated with appropriate antipsychotic therapies and the psychotic symptoms have remitted. Awareness of the potential dangers of combining TCAs with conventional antipsychotics may explain why the combinations most favoured by respondents to this survey consisted of a novel antipsychotic and an SSRI, despite the fact that there are currently no consistent data demonstrating the ecacy of SSRIs in the treatment of depression in schizophrenia. Of interest is the nding that, although uoxetine was the most commonly used antidepressant, 15% of respondents reported that they would actively avoid prescribing this agent. Regarding treatment duration, one-third of respondents indicated that they most frequently prescribed antidepressant therapy for up to 612 months. This may reect a belief among clinicians that they are treating a major depressive episode, rather than depression as part of the general psychosis. Alternatively, it could be indicative of an opinion that the depressive component is a feature of schizophrenia that requires longterm treatment. The respondents cited suicidal ideation, depressed mood, hopelessness, morning depression, guilt and early wakening as the symptoms most likely to prompt the prescription of antidepressant medication. However, only 38% of the respondents routinely used either diagnostic interviews or rating scales for psychosis or depression. Only 25% routinely used a specic depression rating scale. The considerable morbidity associated with depressive symptoms in patients with schizophrenia was acknowledged by the majority of respondents to this survey. The impact on the patient's family was also recognized, with respondents reporting depression in approximately one-third of the carers of those with schizophrenia. However, there are currently no treatment guidelines for dealing with depressive symptoms in schizophrenia. This appears to be reected in the lack of

Clinical issues related to depression in schizophrenia concordance in treatment approaches, with onethird of respondents only rarely or never prescribing antidepressant drugs. Many patients may therefore be receiving suboptimal therapy. Further studies are required in order to proactively deal with this issue and develop appropriate patient management strategies. In addition, the development and distribution of clinical practice guidelines may lead to improvements in identication and eective treatment of depression in time.
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