Vol. 22, No. 4 / November 2010

Differential Diagnosis and Therapeutic Management of Schizoaffective Disorder

• Introduction • Methods • Phenomenology • Etiology/pathophysiology • Assessment and diagnosis • Treatment/ongoing care • Conclusion

Introduction

An estimated 1 of 4 inpatient psychiatry admissions is attributed to schizoaffective disorder (SAD).^1,2 Lifetime prevalence of this important yet poorly understood disorder ranges between 0.5% and 0.8%. Despite its common presentation, few studies with selectively enriched SAD patient populations have been conducted; therefore, information about the phenomenology and treatment of SAD derives more from observational studies or small, post hoc analyses, than from large-scale randomized studies.

SAD is a heterogeneous clinical construct marked by mixed psychotic and affective symptoms, the inter-relationships of which vary considerably between and within individuals, presenting formidable challenges even to experienced psychiatrists.^3,4 The bipolar and depressive subtypes of SAD exert different influences on perception, cognition, affect, mood, and physiological functioning. Knowledge about the clinical features, differential diagnosis, clinical course, and management of SAD has been shaped by diversity of opinion more than by consensus within the field, precluding even the most rudimentary definitions for standard of care. In the American nosology, diagnostic inclusion and exclusion criteria were not specified prior to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). International Classification of Diseases and Related Health Problems 10th revision (ICD-10) criteria for SAD differ in several fundamental respects from those of DSM-IV (Table 1)^3,5 and likely contribute to variations in diagnostic practice in the United States and abroad. The paucity of established treatments for SAD, particularly with agents approved by the U.S. Food and Drug Administration, may further diminish the ability of clinicians to diagnose and treat SAD with confidence.

Until established norms and rigorous treatment standards for SAD are developed, discussion about what constitutes optimal care is premature. Although additional well-designed studies would provide much needed insights into SAD, their enormous cost and length make it unlikely that robust data will be available in the near future. Until a more extensive evidence base emerges to better inform clinical decision making, expert guidance and practice parameters, which help to fill the gaps in knowledge, are critically needed. Accordingly, psychiatrists highly skilled in SAD management convened to foster debate and to exchange their own best practices. Utilizing a modified Delphi process, the SAD Working Group deliberated over their own observations and experience with SAD patients, while comparing and contrasting their views on published studies, which vary considerably by experimental design and rigor. Although initial efforts have included psychiatrists from across the United States, the SAD Working Group hopes to expand the consensus conference globally, underscoring the need for improved therapeutic management of this prevalent and complex disorder.

Methods

The SAD Working Group was convened as a continuing medical education activity accredited by the Albert Einstein Medical Center. Chaired by Henry A. Nasrallah, MD, the Working Group comprises a diverse group of thought leaders with expert insights into the etiology of SAD, strengths and limitations of screening and assessment tools, and current pharmacotherapy and psychosocial interventions. Members of the SAD Working Group utilized a modified Delphi process to draft and refine consensus statements on key issues relevant to the assessment and management of patients with SAD (Appendix). First, the SAD Working Group explored the phenomenology of SAD, consolidating seminal studies on its diagnostic and clinical correlates. Second, evidence-based studies and clinical experience provided the substrate for a clinical framework, outlined by consensus statements of threshold importance and designed to operationalize the recognition, differential diagnosis, and initial and ongoing management of patients with SAD. Third, the clinical utility of the Delphi consensus statements were evaluated at a series of regional workshops, where academic and community-based psychiatrists discussed salient issues in a series of case studies. Feedback from these workshops helped inform the final consensus statements.

Phenomenology

Variations in diagnostic criteria for SAD (DSM-IV TR vs. ICD-10) (Table 1), low inter-rater diagnostic reliability, and limited understanding of the factors that govern its onset, progression, and pathogenesis seriously hinder recognition, diagnosis, and treatment of this complex disorder.^3,5,8 Current diagnostic systems divide psychotic disorders into subtypes, directly conflicting with Kraepelin’s dichotomous classification. Additionally, DSM-IV TR defines SAD as an uninterrupted illness, whereas ICD-10 considers SAD as episodic. Such confounding diagnostic criteria present clinicians with a nosological dilemma, and undermine perceptions of SAD as a unified clinical entity. To date, several classification schemas for SAD have been proffered, reflecting the limited scientific and clinical data. The scope of this report precludes in-depth comparisons of the merits and limitations of these varying descriptions.

SAD has been variously described as a heterogeneous disorder comprising elements of both schizophrenia and bipolar disorders^9,10; a distinct clinical construct unrelated to bipolar disorder or schizophrenia⁷; schizophrenia with mood symptoms¹¹; a mood disorder with psychosis¹²; comorbid schizophrenia and mood disorder¹³; and finally a heterogeneous phenomenon situated on a middle point in a continuum between schizophrenia and mood disorders^14,15 (Table 2). Additional studies are needed to better understand its place in the psychiatric nomenclature, as well as to provide practical knowledge about its recognition and treatment.

Etiology/pathophysiology

Based on empirical observations and varying levels of evidence from clinical studies, the SAD Working Group identified core concepts that define SAD etiopathophysiology. First, the SAD Working Group supports SAD as a clinical construct best described as situated on a continuum between schizophrenia and bipolar disorder. Among authorities in the field—including psychiatrists, clinical researchers, and scientists—there is considerable uncertainty about the relationship of SAD to schizophrenia and mood disorders. Some primarily view SAD as schizophrenia or a psychotic disorder, whereas others argue it is a mood disorder variant. The questions constitute a still emerging area of research, with investigators evaluating genetic, neuroanatomic, and physiologic differences across different patient populations. For example, inherited susceptibility to SAD is attributed to risk alleles. Mansour and coworkers have reported that a variety of genes and risk alleles may be associated with SAD susceptibility and etiology.¹⁶ Genes involved in circadian rhythm and retinoic acid receptor systems, for example, have been linked with SAD.¹⁶ Importantly, variants of these genes are also associated with schizophrenia and bipolar disorder.^16,17 Although incomplete, the data support SAD as a genetic intermediary between bipolar disorder and schizophrenia.

The SAD Working Group identified distinct neuroanatomic and physiologic abnormalities in patients with SAD. Several published studies have reported abnormal saccades, altered evoked potentials, and cognitive impairments in patients with SAD. Computerized measures of memory are significantly different in schizophrenia and SAD patient populations.^18,19 For example, while patients with schizophrenia exhibit pronounced verbal and visuomotor working memory impairments, patients with SAD maintain normal verbal working memory.¹⁸ As SAD is an illness that may change over time, it is important to understand the possible differential diagnostic utility of neurocognitive assessment over extended periods. One study found significant differences between patients with schizophrenia and SAD on motor screening and explicit memory tests during 3 office visits over a period of 19 months.¹⁹ While sufficient studies have not been conducted on the diagnostic utility of neurocognitive and similar discriminative tests, it is hoped that such batteries may eventually serve as clinical assessment tools that facilitate a more accurate diagnosis. Further research will inform clinical recognition and assessment of patients with SAD, promising to optimize differential diagnosis and treatment success.

Assessment and diagnosis

SAD is a psychiatric illness characterized by schizophrenia co-occurring with prominent affective symptomatology consistent with a major mood episode. In addition to cross-sectional symptoms that may be evident on acute presentation, an accurate diagnosis of SAD requires a longitudinal assessment of patient history, particularly psychiatric information, to determine temporal overlap and relative distribution of psychotic and mood symptoms over at least one month. To this end, it is necessary to rely on accurate personal reports of symptoms and behaviors, collateral information, and medical and mental health records. Comprehensive multiaxial physical and neurological examinations can provide important information as well.

Timely recognition and appropriate differential diagnosis of SAD helps individualize treatment. Initial assessment includes consideration of risk factors such as family history and age. Despite the limited data, the SAD Working Group recognizes a family history of psychotic or mood disorders as an important risk factor predictive of SAD. According to results from a recent large-scale study, the relative risk of SAD was 2.76 if a first-degree relative had a history of mental illness compared with control subjects with no with no such family history.²⁰ More precisely, the relative risk of SAD was 3.23, 2.57, or 1.92 if the first-degree relative had bipolar disorder, schizophrenia, or SAD, respectively. Age is another risk factor, especially for the recognition of SAD subtype. Although empirically derived data are lacking, the SAD Working Group concluded that depressive symptoms generally predominate with increasing age, as with bipolar disorder. Long-term studies demonstrating this age-related phenomenon are needed to substantiate the consensus. Conversely, younger patients are more likely to present with manic features, although here, too, the data are largely empirical.

The timing and duration of psychotic and mood symptoms are the most important determinants for an accurate SAD diagnosis. The temporal relationship of psychotic and affective symptoms and proportion of affective symptoms relative to the entire duration of the illness must be ascertained. In addition, clinicians must differentiate negative symptoms from depression and mania from agitation. Whether mood symptoms are of sufficient duration and severity to warrant a diagnosis of SAD in contradistinction to schizophrenia is a common challenge. Further, it is often difficult to determine whether the psychosis occurs only within the context of a mood episode, in which case the diagnosis would be mood disorder with psychotic features rather than SAD. The complex differential diagnosis should address psychosis due to a medical condition, delirium, or dementia; mood symptoms in schizophrenia; mood disorders with psychotic features; and substance-induced psychotic disorder.

Longitudinal history-taking and multiaxial examination are critical determinants for accurate SAD diagnosis. A variety of patient-administered tools are available. Some practitioners may find self-report or clinician-rated assessment tools as useful adjuncts to supplement their clinical interviews. Structured questionnaires, interviews, and rating scales are available to help differentiate SAD subtypes, measure the severity of illness and its impact on patient function, and monitor treatment responsiveness. Although no assessment methods and resources have as yet been validated specifically for SAD, the SAD Working Group nevertheless recommends a variety of tools (Table 3).

Comprehensive assessment provides important biopsychosocial data critical for understanding the SAD patient. Several studies have reported high rates of comorbidity, impaired social, vocational and/or occupational function, and associated reduction in overall quality of life.^21,22 Patients with SAD, for example, have a high prevalence of metabolic syndrome and chronic pulmonary disease.^23,24 Higher rates of coexisting psychiatric morbidities have been reported as well. According to work by Cosoff and Hafner, nearly one-half of all SAD patients (45%; 9/20) had symptoms consistent with comorbid anxiety disorder.²⁵ The SAD Working Group stressed the importance of recognizing and managing medical and psychiatric comorbidities, especially metabolic dysregulation or weight gain, which can be causally related to the illness itself, sedentary lifestyle, unhealthy diet, medication side effects, or a combination of these factors. Medication-related morbidity warrants careful assessment of current and prior medication history. Adjustments to diet, exercise, and/or medications should be considered consistent with patient preferences, goals, and needs.²⁶

For good treatment outcomes, patient assessment is necessarily longitudinal. At times, mood state changes across the life cycle of SAD patients may be particularly dramatic, warranting a change in diagnosis from the depressive to manic subtype, with important implications for multimodal treatment. For some patients, the lability of the mood and psychotic features may manifest across different episodes of the illness separated by a recovery period. For example, an individual may have SAD depressive subtype, fully recover, and after several months develop hallucinations and delusions without prominent mood symptoms for an extended period (eg, 7 months), warranting a change of diagnosis to schizophrenia. This evolution of symptomatology in patients initially diagnosed with SAD is not uncommon. According to a seminal 2-year study, only 36% (12/33) of patients initially diagnosed with SAD continued to meet DSM-IV diagnostic criteria for the illness.²⁷ After 2 years, the predominant diagnostic changes were to major depressive disorder (26%, 27/103), followed by bipolar disorder (17%; 24/141) and finally schizophrenia (8%; 12/145). In a separate, 5-year, retrospective study, 61% of patients initially diagnosed with SAD (37/61) were subsequently diagnosed with bipolar disorder.²⁸ In addition to the age-related instability of subtypes, SAD is the most commonly revised diagnosis in patients with psychotic features. One large-scale study found that 22.4% (112/500) of patients had a different diagnosis 2 years after their initial diagnosis; SAD represented the most changed-to diagnosis (53.6%; 60/112).²⁹ The results of these studies are consistent with the instability of an SAD diagnosis and highlight the benefits of longitudinal assessment and need to restructure treatment accordingly

Treatment/ongoing care

Reflecting an inadequate understanding of the biologic basis and clinical correlates of SAD, treatment strategies have received little attention in the peer-reviewed literature and evidence-based guidelines. Only a handful of well-controlled studies have investigated the efficacy of pharmacologic or psychotherapeutic approaches in well-defined SAD patient populations. Clinicians necessarily draw tentative conclusions from studies of mixed patient populations—including, for instance, SAD and schizophrenia—that demonstrate significantly improved outcomes.

The primary objective of pharmacotherapy is to achieve symptomatic control. As with virtually all psychiatric disorders, best patient outcomes are achieved by multimodal therapy, usually a combination of pharmacologic agents with psychotherapeutic or psychosocial modalities. Atypical antipsychotics are currently the mainstay of pharmacotherapy for SAD, although more studies are needed to establish their efficacy, particularly in patients with complex, evolving symptomatology. Acute and maintenance therapy are guided by results from longitudinal, multiaxial assessment, from experience in managing this sometimes difficult-to-treat patient population, and from good clinical judgment. Accompanying this monograph is an evidence-based conceptual framework and consolidated resource that will, when applied on a patient-by-patient basis, help structure the decision making process for patients with SAD.

Selecting an appropriate atypical antipsychotic requires adequate physician-patient dialogue, patient and family education, treatment adherence, and thoughtful assessment and management of adverse events. Careful review of the available evidence provides essential, albeit limited, guidance. For example, randomized controlled trials of atypical antipsychotic monotherapy in mixed samples of SAD and schizophrenia patients have shown significant improvements in symptoms, social rehabilitation, and quality of life when compared to patients treated with typical antipsychotics.^21,30 Only 2 randomized, double-blind, placebo-controlled studies of an atypical antipsychotic (paliperidone extended-release, now FDA-approved for the treatment of SAD), have been conducted in a well-defined SAD patient population (Figure).³¹ Treatment was well-tolerated and conferred significant benefits across numerous psychiatric, functional, mood, and quality of life domains as measured by the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions Scale (CGI-S), Young Mania Rating Scale (YMRS), and Hamilton Depression Rating Scale (HAM-D).^31-35 In a randomized, placebo-controlled study in patients with SAD, Keck and coworkers reported improved mean scores in ziprasidone-treated patients as per the Brief Psychiatric Rating Scale (BPRS) total, BPRS core, BPRS manic, and mean CGI-S scales.³⁶ Reflecting the infancy of comparative effectiveness research in general, few studies with SAD patients have utilized active controls. In 2 older studies, olanzapine demonstrated superior efficacy when compared to haloperidol, while another study showed significantly improved side-effect profiles in risperidone-treated patients compared with those receiving haloperidol.^37-39

Other published studies supporting the safety and efficacy of atypical antipsychotics in SAD patients are limited by their focus on patients with schizophrenia and/ or bipolar disorder, and by their post hoc analyses of SAD subgroups. Available data are limited also by the heterogeneity of SAD itself; studies often included patients with established bipolar and depressive subtypes without prospectively defined and subtype-specific endpoints. Still other variations in experimental design—including study duration, size, methodology, and outcome measures—also limit the conclusions (and recommendations) that the SAD Working Group can make.⁴⁰ Consensus on important treatment issues did emerge, nonetheless.

Among the clear points of consensus is that acute management of psychotic symptoms in SAD patients should include antipsychotic therapy. The SAD subtype influences pharmacologic approaches to maintenance treatment, however. Although all patients with SAD are generally prescribed an antipsychotic, there is debate about the value of adjunctive antidepressants or mood stabilizers such as lithium or divalproex.^30,41-43 Nevertheless, based at least in part on their experience managing patients with bipolar disorder, the SAD Working Group recommends addition of a mood stabilizer in patients with SAD bipolar subtype, at least when manic symptoms do not adequately respond to antipsychotic treatment alone.

Randomized controlled trials have evaluated rational multi-drug therapy, with inconclusive findings, although most viewed atypical antipsychotics as first-line treatment for SAD, particularly during acute episodes.^30,44,45 Two randomized controlled trials have shown measurable benefits of mood stabilizers in patients with SAD. In an older trial, fluphenazine proved superior to lithium in patients with SAD depressive subtype, and carbamazepine demonstrated superior prophylactic efficacy when compared to lithium in patients with SAD bipolar subtype.^46,47 Limited evidence precludes definitive conclusions regarding the role of antidepressants, yet the SAD Working Group concluded that the addition of an antidepressant is reasonable when depressive symptoms persist following stabilization of psychosis.

Most of the psychiatrists in the SAD Working Group emphasized that non-pharmacologic therapies should generally be used in combination with pharmacologic agents to achieve the greatest benefit, although the notion of additive and potentially supra-additive effects is based on empirical observations alone. Psychosocial interventions, which often include the patient with select family members, friends, partners, and caregivers, can enhance patient insight into the illness, teach appropriate social skills, and restore vocational functioning. Cognitive-behavioral therapy (CBT) can help patients understand the relationship between their feelings, maladaptive patterns of thinking, and distress. Over time, CBT helps patients develop adaptive behaviors and routines that improve adherence to the prescribed regimen, a linchpin for sustained efficacy. Along these lines, psychoeducation can help raise patient awareness about the illness and appropriate treatment options. Patients are educated, for instance, about treatment-related side effects, timing of dosing, and other particulars that can prove daunting to patients with impaired cognition and executive function.

Patients with SAD tend to respond to treatment better than those with schizophrenia, although SAD is associated with significantly worse outcomes compared with bipolar disorder or major depression.¹⁵ As with all psychiatric disorders, maximizing treatment adherence in patients with SAD is a critical determinant of treatment success.⁴⁸ For reasons only partly understood, SAD and schizophrenia patients have similarly low treatment adherence rates. In 1 study, only 59% (8,557/16,570) of SAD patients were at least moderately adherent to antipsychotic therapy as indicated by their medication possession ratio, defined as the number of days of medication dispensed as a percentage of the 180-day study period.^24,49 These adherence data are consistent with previously published studies of patients with schizophrenia.⁵⁰ Strategies designed to promote treatment adherence in patients with psychiatric disorders include psychoeducation, motivational interviewing, simplification of prescribed regimens, the use of calendars to self-monitor treatment adherence, maintenance of routines such as dosing times, and supervised medication intake.⁴⁸ Antipsychotic pharmacokinetic and pharmacodynamic profiles also play an important role. Poor tolerability may discourage patients from taking medications. Finally, studies have demonstrated improved adherence and patient outcomes with simplified medication regimens and long-acting injectable antipsychotic formulations.^51-53

Conclusion

Although significant advances have been made in our understanding of the biopsychosocial basis of SAD, little is known about this clinical construct, and evidence-based approaches to the assessment, diagnosis, and treatment of patients with SAD are limited. Patients with SAD often present with a complex combination of psychotic and affective symptoms. Differential diagnosis of SAD and its subtypes is challenging, reflecting inconsistent diagnostic criteria; a paucity of clearly demarcated genetic, neuropsychological, or neurophysiological determinants; and an often-evolving clinical presentation that shares features with schizophrenia and bipolar disorder. Evidence supporting diagnosis and treatment is limited and clinicians rely largely on a handful of well-designed studies, experience, and case study reports. Accordingly, the SAD Working Group has formulated consensus statements (Appendix) that define the current state of knowledge and practice consistent with the available evidence and expert opinion. Diagnosis is aided by numerous assessment tools, none of which has been specifically validated for the SAD patient population. Treatment with atypical antipsychotics is generally considered necessary for symptomatic control, with less uniform agreement on the role and duration of therapy with traditional mood stabilizers or antidepressants. A variety of adjunctive nonpharmacologic modalities may help to foster medication adherence and improve overall outcomes. Many patients struggle to maintain adherence to their multimodal regimens, owing in part to the nature of the illness and intolerability to the pharmacotherapy. Switching compounds within the atypical class to improve tolerability and/or reduce the frequency of daily dosing, or choosing long-acting injectable formulations may, on a patient by patient basis, further help improve adherence.

References

1. Azorin JM, Kaladjian A, Fakra E. Current issues on schizoaffective disorder. Encephale. 2005;31(3):359–365.
2. Kent S, Fogarty M, Yellowlees P. Heavy utilization of inpatient and outpatient services in a public mental health service.Psychiatric services (Washington, D.C.).1995;46(12):1254–1257.
3. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
4. Kempf L, Hussain N, Potash JB. Mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features: trouble at the borders. Int Rev Psychiatry. 2005;17(1):9–19.
5. The ICD-10 classification of mental and behavioural disorders.Diagnostic criteria for research. Geneva: World Health Organization; 1993.
6. Perala J, Suvisaari J, Saarni SI, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007;64(1):19–28.
7. Tsuang MT. Morbidity risks of schizophrenia and affective disorders among first-degree relatives of patients with schizoaffective disorders. Br J Psychiatry. 1991;158(2):165–170.
8. Maj M, Pirozzi R, Formicola AM, et al. Reliability and validity of the DSMIV diagnostic category of schizoaffective disorder: preliminary data. J Affect Disord. 2000;57(1-3):95–98.
9. Levitt JJ, Tsuang MT. The heterogeneity of schizoaffective disorder: implications for treatment. Am J Psychiatry. 1988;145(8):926–936.
10. Tsuang D, Coryell W. An 8-year follow-up of patients with DSM-III-R psychotic depression, schizoaffective disorder, and schizophrenia. Am J Psychiatry. 1993;150(8):1182–1188.
11. Evans JD, Heaton RK, Paulsen JS, et al. Schizoaffective disorder: a form of schizophrenia or affective disorder? J Clin Psychiatry. 1999;60(12):874–882.
12. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol. 1996;16(2 Suppl 1):4S–14S.
13. Kendler KS, McGuire M, Gruenberg AM, et al. Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon Family Study. Am J Psychiatry. 1995;152(5):755–764.
14. Crow TJ. Nature of the genetic contribution to psychotic illness—a continuum viewpoint. Acta Psychiatr Scand. 1990;81(5):401–408.
15. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. Does schizoaffective disorder really exist? A systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders. J Affect Disord. 2008;106(3):209–217.
16. Mansour HA, Talkowski ME, Wood J, et al. Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia. Bipolar Disord. 2009;11(7):701–710.
17. Potash JB. Carving chaos: genetics and the classification of mood and psychotic syndromes. Harv Rev Psychiatry. 2006;14(2):47–63.
18. Gruber O, Gruber E, Falkai P. Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder. Neurosci Lett. 2006;405(1-2):24–28.
19. Stip E, Sepehry AA, Prouteau A, et al. Cognitive discernible factors between schizophrenia and schizoaffective disorder. Brain Cogn. 2005;59(3):292–295.
20. Laursen TM, Labouriau R, Licht RW, et al. Family history of psychiatric illness as a risk factor for schizoaffective disorder: a Danish register-based cohort study. Arch Gen Psychiatry. 2005;62(8):841–848.
21. Golubovic B, Misic-Pavkov G, Gajic Z, et al. Evaluation of quality of life for patients with schizophrenic and schizoaffective disorders related to the use of antipsychotic therapy. Med Arh. 2010;64(1):37–40.
22. Hasson-Ohayon I, Kravetz S, Meir T, et al. Insight into severe mental illness, hope, and quality of life of persons with schizophrenia and schizoaffective disorders. Psychiatry Res. 2009;167(3):231–238.
23. Basu R, Brar JS, Chengappa KN, et al. The prevalence of the metabolic syndrome in patients with schizoaffective disorder—bipolar subtype. Bipolar Disord. 2004;6(4):314–318.
24. Olfson M, Marcus SC, Wan GJ. Treatment patterns for schizoaffective disorder and schizophrenia among Medicaid patients.Psychiatric services (Washington, D.C.).2009;60(2):210–216.
25. Cosoff SJ, Hafner RJ. The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder. Aust N Z J Psychiatry. 1998;32(1):67–72.
26. Maayan L, Correll CU. Management of antipsychotic-related weight gain. Expert Rev Neurother. 2010;10(7):1175–1200.
27. Schwartz JE, Fennig S, Tanenberg-Karant M, et al. Congruence of diagnoses 2 years after a first-admission diagnosis of psychosis. Arch Gen Psychiatry. 2000;57(6):593–600.
28. Salvatore P, Baldessarini RJ, Tohen M, et al. McLean-Harvard International First-Episode Project: two-year stability of DSM-IV diagnoses in 500 first-episode psychotic disorder patients. J Clin Psychiatry. 2009;70(4):458–466.
29. Nardi AE, Nascimento I, Freire RC, et al. Demographic and clinical features of schizoaffective (schizobipolar) disorder—a 5-year retrospective study. Support for a bipolar spectrum disorder. J Affect Disord. 2005;89(1-3):201–206.
30. Levinson DF, Umapathy C, Musthaq M. Treatment of schizoaffective disorder and schizophrenia with mood symptoms. Am J Psychiatry. 1999;156(8):1138–1148.
31. Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, et al. A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder. J Clin Psychiatry. 2010;71(5):587–598.
32. Rabinowitz J, Levine S, Martinez G. Concordance between measures of functioning, symptoms, and change: examining the GAF, CGI-S, CGI-C, and PANSS. J Clin Psychopharmacol. 2010;30(4):478–480.
33. Canuso CM, Schooler N, Kosik-Gonzalez C, et al. A randomized, double-blind, placebo-controlled study of flexible-dose paliperidone ER in the treatment of patients with schizoaffective disorder.Paper presented at: International Congress on Schizophrenia Research; Mar 28-Apr 1, 2009; San Diego, CA.
34. Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, et al. A randomized, double-blind, placebo-controlled study of paliperidone ER in the treatment of subjects with schizoaffective disorder [poster].Paper presented at: U.S. Psychiatric and Mental Health Congress; Oct 30-Nov 2, 2008; San Diego, CA.
35. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276.
36. Keck PE Jr., Reeves KR, Harrigan EP. Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double-blind, placebo-controlled, multicenter studies. J Clin Psychopharmacol. 2001;21(1):27–35.
37. Tohen M, Zhang F, Keck PE, et al. Olanzapine versus haloperidol in schizoaffective disorder, bipolar type. J Affect Disord. 2001;67(1-3):133–140.
38. Tran PV, Tollefson GD, Sanger TM, et al. Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Acute and long-term therapy. Br J Psychiatry. 1999;174:15–22.
39. Janicak PG, Keck PE Jr., Davis JM, et al. A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder. J Clin Psychopharmacol. 2001;21(4):360–368.
40. Jager M, Becker T, Weinmann S, et al. Treatment of schizoaffective disorder—a challenge for evidence-based psychiatry. Acta Psychiatr Scand. 2009;121(1):22–32.
41. Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67(4):509–516.
42. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005;66(1):111–121.
43. Hirschfeld RM, Keck PE Jr., Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161(6):1057–1065.
44. McElroy SL, Keck PE Jr., Strakowski SM. An overview of the treatment of schizoaffective disorder. J Clin Psychiatry. 1999;60 (Suppl 5):16–21;discussion 22.
45. Mensink GJ, Slooff CJ. Novel antipsychotics in bipolar and schizoaffective mania. Acta Psychiatr Scand. 2004;109(6):405–419.
46. Mattes JA, Nayak D. Lithium versus fluphenazine for prophylaxis in mainly schizophrenic schizo-affectives. Biol Psychiatry. 1984;19(3):445–449.
47. Greil W, Ludwig-Mayerhofer W, Erazo N, et al. Lithium vs carbamazepine in the maintenance treatment of schizoaffective disorder: a randomised study. Eur Arch Psychiatry Clin Neurosci. 1997;247(1):42–50.
48. Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(Suppl 4):1–46; quiz 47-48.
49. Valenstein M, Copeland LA, Blow FC, et al. Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care. 2002;40(8):630–639.
50. Valenstein M, Blow FC, Copeland LA, et al. Poor antipsychotic adherence among patients with schizophrenia: medication and patient factors. Schizophr Bull. 2004;30(2):255–264.
51. Peuskens J, Olivares JM, Pecenak J, et al. Treatment retention with risperidone long-acting injection: 24-month results from the Electronic Schizophrenia Treatment Adherence Registry (e-STAR) in six countries. Curr Med Res Opin. 2010;26(3):501–509.
52. Diaz E, Neuse E, Sullivan MC, et al. Adherence to conventional and atypical antipsychotics after hospital discharge. J Clin Psychiatry. 2004;65(3):354–360.
53. Chengappa KN, Parepally H, Brar JS, et al. A random-assignment, double-blind, clinical trial of once- vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study. Can J Psychiatry. 2003;48(3):187–194.
54. Gelenberg AJ. Using assessment tools to screen for, diagnose, and treat major depressive disorder in clinical practice. J Clin Psychiatry. 2010;71;(Suppl E1):e01.
55. Young RC, Biggs JT, Ziegber VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435.
56. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.
57. Sharp LK, Lipsky MS. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Physician. 2002;66(6):1001–1008.

Annals of Clinical Psychiatry ©2010 Quadrant HealthCom Inc.