Schizophrenia may be medicine's prime example of a diversity of clinical manifestations within a single diagnostic class.'
Depression, obsessive-compulsive disorder, and panic disorder are widely present in schizophrenia and appear to account for some of its clinical heterogeneity.2 Evidence suggests that associated psychiatric syndromes may adversely affect the clinical course of schizophrenia, are temporally stable, and may be treatable. These features make associated psychiatric syndromes candidates for a role in subtyping. This article reviews what is required of a subtyping system and then outlines some of what is known about associated psychiatric syndromes with an emphasis on those qualities that invite speculation about their potential role in subtyping schizophrenia.
The clinical heterogeneity of schizophrenia has led to a search for meaningful subtypes.1 Subtyping is a necessary strategy to establish homogeneous groupings3 for any biologic research. More than a research tool, a subtyping system should also assist clinicians by providing (1) treatment guidance, (2) consistency of clinical course or prognosis, and (3) enhanced communication about patients.4 An individual patient's subtype should remain relatively constant, as it should reflect underlying disease process(es). Also, subtypes should be passed to progeny at greater than random rates (ie, they should "breed true"). Current subtypes have an uneven record in meeting these varied requirements. Shortcomings in the system to subdivide schizophrenia have probably contributed to the widespread tendency to treat the illness as if it were a single, unitary entity.2
The utility of current and traditional schizophrenia subtypes (catatonic, disorganized, paranoid, and undifferentiated) has been a subject of debate5"7 because they do not remain stable over time and do not consistently breed true.8"10 The paranoid subtype, thought to predict better outcome and to reflect better premorbid adjustment,11 has had its validity questioned.12"15 The classic subtypes have been criticized for being "temporally unstable, phenomenologically nonspecific and of dubious validity."4 These subtypes offer little prognostic information and may change considerably over time. They also offer little treatment guidance; generally, patients with schizophrenia are given antipsychotics that are adjusted for symptom severity independent of their subtype.
A relatively recent attempt to subclassify schizophrenia was based on the distinction between negative and positive symptoms.16,17 Liddle18 added a disorganization factor to this, based on factor analysis.
To study the problem of change in subtype over time, McGlashan and Fen ton19 reviewed data from the Chestnut Lodge follow-up study and found that "during the first 5 years of manifest illness, the subtype phenomenologies were moderately stable. Instability consisted of a drift toward disorganization (hebephrenia) and nonspecificity (undifferentiated) among the classical subtypes, and toward the deficit subtype within that categorization."
With the use of the subtyping standards of treatability, effect on prognosis, and temporal stability, associated psychiatric syndromes may provide a useful framework for a clinical approach to subtyping. Associated psychiatric syndromes may offer strengths in some of those areas where the classic subtypes appear to be weak.
WHAT ARE ASSOCIATED PSYCHIATRIC SYNDROMES?
Depression,20 obsessive-compulsive disorder,21"23 and panic disorder24"26 frequently occur with schizophrenia. Hierarchical concepts of nosology in the DSM system have limited the diagnosis of these syndromes in schizophrenia.2 A coexisting anxiety or depressive disorder that is "better accounted for" by the schizophrenia may not be diagnosed in the DSM-IV.5 This has contributed to a relative neglect of these widely prevalent syndromes.2,27 Few studies of their validity, including their treatability, heritability, and effect on course and outcome in schizophrenia, have been conducted. Too little is known about these syndromes relative to their prevalence in schizophrenia.
Of the three associated psychiatric syndromes considered in this article, depression has been the most extensively studied, and the lessons learned from this work may help guide the study of obsessive-compulsive disorder and panic disorder in schizophrenia. Depression was long thought to be rare in or even incompatible with schizophrenia.20 However, it can be diagnosed and treated in patients with schizophrenia. The inclusion of post-psychotic depression in the DSM-IV reflects a growing recognition of this clinical entity. The increased study of panic disorder and obsessive-compulsive disorder in schizophrenia may also lead to improved recognition of these syndromes.
Eighty-five percent (17 of 20) of the patients with schizophrenia identified in a random community sample had one or more of these three associated psychiatric syndromes.27 The lifetime rates of depression, obsessive-compulsive disorder, and panic disorder were 54.2%, 59.2%, and 29.5%, respectively, in this study. As a result of intensive, standardized interviews, Bermanzohn et al.2 reported that 18 (48.6%) of 37 patients with chronic schizophrenia studied in a day treatment program had one or more associated psychiatric syndromes. Ten patients (27%) had major depression, 11 patients (29.7%) met criteria for obsessive-compulsive disorder, and 4 patients (10.8%) exhibited panic disorder. Although some of these diagnoses were made in violation of the DSM-JVs exclusion rules, the conditions of several patients improved when they were openly treated for these syndromes with an appropriate agent.
The modal prevalence rate published for depression in schizophrenia is 25%. 20 Martin et al.28 found that nearly 60% of patients with schizophrenia had at least one depressive episode during the course of their lives. Prevalence rates for obsessive-compulsive disorder in schizophrenia have also varied widely, with most of the reported rates ranging from 20% to 30%.29 Panic disorder has been reported in from 11 %2 to 63%24 of those individuals with schizophrenia, but a modal rate has not emerged.
Temporal Stability and Precipitation of Psychosis
Associated psychiatric syndromes appear to be stable over time, but currently this is based on retrospective studies only. In patients with schizophrenia and obsessive-compulsive disorder, onset of the obsessive-compulsive disorder preceded schizophrenia in most cases where a determination of this could be made.21,27 Likewise, in those cases where they coexisted, panic disorder usually preceded the onset of schizophrenia (D. S. Rae, MA, J. Reich, MD, MPH, P. B. Arlow, MSW, et al., unpublished data, 1999).27
Siris has suggested that associated psychiatric syndromes may act as endogenous stressors, initiating or exacerbating psychosis.30 Several lines of evidence support this view. Obsessive-compulsive disorder and social phobia were significant predictors (P = .0072 and P = .0024, respectively) and panic disorder a weak predictor (P = .062) of an increased risk for development of schizophrenia in the two waves of the Epidemiologic Catchment Area study.31 Depressed patients with schizophrenia treated with Imipramine had fewer psychotic relapses than did those treated with placebo, suggesting that antidepressant therapy might protect such patients from relapse into psychosis.32
Depression,33 obsessive-compulsive symptoms,21'22'34 and, more generally, anxiety disorders35 have been associated with poorer outcomes in patients with schizophrenia. Some studies36"38 found that patients with obsessivecompulsive disorder plus schizophrenia had evidence of higher functioning than did patients with schizophrenia but without obsessive-compulsive disorder. The subject of the effect of depression on functional outcome in schizophrenia has been controversial.39 To the author's knowledge, the effect of panic disorder on the clinical course of schizophrenia has not been examined. However, because panic disorder, similar to other associated psychiatric syndromes, can be disabling without schizophrenia,40 this author hypothesizes that it may cause further disability among patients who also have schizophrenia.
DIFFICULTY RECOGNIZING ASSOCIATED PSYCHIATRIC SYNDROMES
Active psychosis may obscure other psychopathology and is often a more urgent clinica! priority for treatment.41 But even in clinically stable patients with schizophrenia, associated psychiatric syndromes may overlap significantly with schizophrenic psychopathology, making it difficult to distinguish them.2 Depression may he difficult to separate from the negative symptoms of schizophrenia, as both are characterized by low energy, diminished interest, lack of pleasure, decreased drive state, reduced motor activity, impaired concentration, and a general sense of helplessness.42'43 Obsessions sometimes overlap with delusions, as both rest on improbable or excessive ideas.44 Panic can share features with paranoia, as both include extreme anxiety coupled with the mistaken but persistent belief that one is in danger, which might lead to social isolation (D. S. Rae, MA, J. Reich, MD, MPH, P. B. Anow, MSW, unpublished data, 1999). Bermanzohn et al. found a strong statistical association between panic and paranoia in schizophrenia in the Epidemiologic Catchment Area study data that they attributed in part to syndromal overlap between the two conditions.
Side effects of antipsychotics may mimic features of associated psychiatric syndromes, further complicating their recognition. Conventional antipsychotics may produce akinesia or akathisia, which may be difficult to distinguish from depression.20 Akathisia may also be difficult to distinguish from anxiety states, including panic.45 Finally, atypical antipsychotic agents, especially clozapine and risperidone, have been implicated in the initiation or exacerbation of obsessivecompulsive disorder; however, this assertion is controversial.46
TREATMENT OF ASSOCIATED PSYCHIATRIC SYNDROMES
Difficulty recognizing associated psychiatric syndromes may help to explain the scarcity of studies on the treatment of them. Depression in schizophrenia has been treated in controlled trials using imiprarnine and amitriptyline, with improvement on active treatment compared with placebo.20 Treatment of obsessive-compulsive disorder and panic disorder in schizophrenia has not been as well studied as treatment of depression in schizophrenia. Five small case series and anecdotal reports using pharmacologic treatment for obsessive-compulsive disorder plus schizophrenia have been published. All of these case series added domipramine to patients' antipsychotic medication regimens, but only one of them was controlled.117 Several oí these studies found that psychotic symptoms improved along with the obsessive-compulsive symptoms. Although promising, none of these studies is definitive.48 A single case in which cognitive-behavioral therapy was used for a patient with obsessive-compulsive disorder, hallucinations, and delusions who appeared to meet criteria for schizophrenia has also been reported,49 but these psychotic symptoms were thought to be related to the obsessive-compulsive disorder (I. Marks, PhD, personal communication, September 19, 1997).
No controlled trials for the treatment of panic have been published. In one study, panic improved with the addition of and worsened with the removal of alprazolam, which was openly administered, then tapered, and then withdrawn in a standardized treatment protocol given to seven hospitalized patients with chronic panic and schizophrenia.50 Both negative and positive symptoms of schizophrenia improved and worsened along with the changes in panic symptomatology. Alprazolam and imipramine have been successfully used for panic in schizophrenia in small case series.51 Cognitive-behavioral therapy has been used in several trials, including two in group settings52,53 and another in a series of individual cases.54
Both pharmacologic and behavioral approaches need to be tested for their efficacy in treating associated psychiatric syndromes. The few studies conducted so far have generally been positive, suggesting that this area has potential. If these syndromes prove to be treatable, clinicians may be better able to individualize treatment for patients with schizophrenia who have them.
Associated psychiatric syndromes need to be validated in treatment trials. They also need to be studied for their effect on prognosis and for their heritability. Based on what is being learned, associated psychiatric syndromes appear to offer a promising approach to the clinical subtyping of schizophrenia.
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