A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia.

OBJECTIVE: This study determined if augmentation of neuroleptics with 3 g/day of ethyl eicosapentaenoic acid (EPA) improves symptoms and cognition in patients with schizophrenia or schizoaffective disorder. METHOD: Eighty-seven patients meeting criteria for schizophrenia or schizoaffective disorder who had residual symptoms despite neuroleptic treatment were randomly assigned to receive either 3 g/day of ethyl EPA (N=43) or placebo (N=44) in a 16-week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 1, 2, 4, 8, 12, and 16; a cognitive battery was administered at baseline and at week 16. RESULTS: No differences were found between groups in positive or negative symptoms, mood, cognition, or global impression ratings. Results were similar for the intention-to-treat (N=87) and completer (N=75) groups. CONCLUSIONS: For schizophrenia patients treated with 3 g/day of ethyl EPA, improvement in residual symptoms and cognitive impairment was no greater than for schizophrenia patients treated with placebo.

Informed Consent in Early Psychosis Research: National Institute of Mental Health workshop, November 15, 2000.

Recent research on the early detection and treatment of schizophrenia has generated significant scientific interest along with considerable controversy and debate. Because our ability to alleviate fully the symptoms and deficits of established schizophrenia is limited, the prospect of interrupting disease progression early is compelling. At the same time, in the absence of an infallible marker of disease risk, there are serious questions about the safety, feasibility, and ethics of intervention research on "at-risk" or putatively prodromal individuals. A workshop, Informed Consent in Early Psychosis Research, was convened by the National Institute of Mental Health (NIMH) on November 15, 2000, to review the results of recent research on early detection and intervention in schizophrenia. Beginning with the assumptions that (1) treatment of asymptomatic individuals with antipsychotic medication is not appropriate in research or clinical care, and (2) neither data nor clinical consensus defines optimal intervention for symptomatic at-risk individuals, workshop participants-including clinical researchers, mental health consumers and family members, bioethicists, community health care providers, and NIMH staff-systematically reviewed available data on the potential risks and benefits of alternate approaches to the management of prodromal states. Ethical issues involved in early detection and intervention studies were discussed. Workshop participants summarized information presented during the meeting into informed consent "bullets" that must be communicated to, and understood and appreciated by, potential research participants.

Depression, suicide, and suicide prevention in schizophrenia.

Suicide is the single largest cause of premature death among individuals with schizophrenia. Furthermore, epidemiological data indicate that nearly 80% of patients with the diagnosis of schizophrenia will experience a major depressive episode at some time during their lifetime. This report reviews recent findings relative to the risk of suicide in schizophrenia, including data from the Chestnut Lodge longitudinal study of schizophrenia subtypes and symptom domains. Paradoxically, those patients with schizophrenia who are most likely to recover or experience a good outcome are also those at greatest risk for suicide. The reduction of morbidity and mortality in schizophrenia should include depression and suicidality as targets for both psychopharmacological and psychosocial treatment.

Prevalence of spontaneous dyskinesia in schizophrenia.

Spontaneous abnormal involuntary movements phenomenologically identical to neuroleptic-induced tardive dyskinesia have been described in schizophrenia for over a century. Because at present nearly all patients with schizophrenia are exposed to neuroleptic medications, information about the prevalence of spontaneous dyskinesia is obtained from accounts from the preneuroleptic era, evaluations of first-episode patients before neuroleptic treatment, and the identification and assessment of drug-naive patients in developing countries. In this report, data from 14 studies of neuroleptic-naive patients with schizophrenia are used to generate age-adjusted estimates of the prevalence of spontaneous dyskinesia. While the precision of this estimate is limited by the difficulty of obtaining large, untreated samples, available data suggest a spontaneous dyskinesia rate of approximately 4% in first-episode schizophrenic patients, 12% for patients ill several years but below age 30 years, 25% for those aged between 30 and 50 years, and 40% for those aged 60 years or older. Relative to the incidence and accrued prevalence of spontaneous dyskinesia expected during the natural history of untreated schizophrenia, the cumulative impact of treatment with new neuroleptic agents has yet to be determined.

Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia.

Recent research suggests that deficient uptake or excessive breakdown of membrane phospholipids may be associated with schizophrenia. We review available clinical research on abnormalities in membrane fatty acid composition and metabolism in schizophrenia, and therapeutic trials of fatty acid in this disorder. All potentially relevant English-language articles were identified from the medical and psychiatric literature with the aid of computer searches using key words such as lipids, phospholipids, prostaglandins and schizophrenia. All studies which include human subjects are reviewed. Empirical studies related to membrane hypotheses of schizophrenia focus on: 1) assessment of prostaglandins (PG) and their essential fatty acid (EFA) precursors in the tissues of patients with schizophrenia; 2) evaluation of the niacin flush test as a possible diagnostic marker; 3) evaluation of phospholipase enzyme activity; 4) NMR spectroscopy studies of brain phospholipid metabolism; and 5) therapeutic trials of PG precursors for the treatment of schizophrenia. The most consistent clinical findings include red blood cell fatty acid membrane abnormalities, NMR spectroscopy evidence of increased phospholipid turnover and a therapeutic effect of omega-3 fatty acid supplementation of neuroleptic treatment in some schizophrenia patients. Studies of EFA metabolism have proved fruitful for generating and testing novel etiologic hypotheses and new therapeutic agents for schizophrenia. Greater attention to factors that influence tissue EFA levels such as diet, tobacco and alcohol are required to reconcile inconsistent findings. Treatment studies, although promising, require independent replication.

Evidence-based psychosocial treatment for schizophrenia.

Current recommendations for evidence-based schizophrenia treatment support a comprehensive, individualized approach that integrates advances in psychopharmacology with psychosocial strategies for disease management. In this issue of the Schizophrenia Bulletin, we invited clinician investigators to summarize new empirical data concerning the efficacy of psychosocial interventions that target common and particularly problematic aspects of schizophrenia. A rich formulary of psychosocial interventions with demonstrated efficacy is now available. With new neuroleptic medications, these interventions should define the current standard of care for schizophrenia.

Evolving perspectives on individual psychotherapy for schizophrenia.

Some form of individual psychotherapy, in combination with the prescription of antipsychotic medications, is likely the most common treatment for patients with schizophrenia. In the absence of empirical data supporting the efficacy of a particular approach, psychotherapy has often been guided by ideology and deference to authority. In recent years, a reformulation of schizophrenia as a disorder requiring individualized, comprehensive treatment has allowed the development and empirical testing of new targeted and illness-phase-specific individual psychotherapies. This report reviews randomized clinical trials that have evaluated individual psychotherapy of schizophrenia in the context of changing contemporaneous beliefs about the disorder's etiology and treatment. A general approach to individual treatment, termed "flexible psychotherapy," derived from historical approaches but consistent with available clinical and research perspectives, is outlined.

Randomized trial of general hospital and residential alternative care for patients with severe and persistent mental illness.

OBJECTIVE: Severe and persistent mental illnesses are often lifelong and characterized by intermittent exacerbations requiring hospitalization. Providing needed care within budgetary constraints to this largely publicly subsidized population requires technologies that reduce costly inpatient episodes. The authors report a prospective randomized trial to test the clinical effectiveness of a model of acute residential alternative treatment for patients with persistent mental illness requiring hospital-level care. METHOD: Patients enrolled in the Montgomery County, Md., public mental health system who experienced an illness exacerbation and were willing to accept voluntary treatment were randomly assigned to the acute psychiatric ward of a general hospital or a community residential alternative. There were no psychopathology-based exclusion criteria. Treatment episode symptom improvement, satisfaction, discharge status, and 6-month pre- and postepisode acute care utilization, psychosocial functioning, and patient satisfaction were assessed. RESULTS: Of 185 patients, 119 (64%) were successfully placed at their assigned treatment site. Case mix data indicated that patients treated in the hospital (N = 50) and the alternative (N = 69) were comparably ill. Treatment episode symptom reduction and patient satisfaction were comparable for the two settings. Nine (13%) of 69 patients randomly assigned to the alternative required transfer to a hospital unit; two (4%) of 50 patients randomly assigned to the hospital could not be stabilized and required transfer to another facility. Psychosocial functioning, satisfaction, and acute care use in the 6 months following admission were comparable for patients treated in the two settings and did not differ significantly from functioning before the acute episode. CONCLUSIONS: Hospitalization is a frequent and high-cost consequence of severe mental illness. For patients who do not require intensive general medical intervention and are willing to accept voluntary treatment, the alternative program model studied provides outcomes comparable to those of hospital care.

Prevalence of spontaneous dyskinesia in schizophrenic and non-schizophrenic psychiatric patients.

BACKGROUND: Although movement disorders have been noted among patients never exposed to neuroleptic medications, the specificity of spontaneous dyskinesia to schizophrenia has rarely been examined. METHOD: By abstracting detailed case records, we compared the prevalence of dyskinetic movements between 94 neuroleptic-naïve schizophrenic patients and 179 patients with other psychiatric disorders. RESULTS: Dyskinetic movements were more common among patients with schizophrenia than among those with all other diagnoses, and were most often noted in the body areas typically associated with tardive dyskinesia. CONCLUSIONS: Spontaneous dyskinesia appears to be relatively specific to schizophrenia and may be intrinsic to the pathophysiology of the disorder.

Line drawing as a possible measure of lateralized motor performance in schizophrenia.

In this paper we suggest a new method, conceived by Maher, to assess lateralized motor performance in schizophrenia. Subjects draw two straight lines with each hand. The lines are scanned into a computer, and a regression is run on the points of the line. The root mean squared error (RMS) of the regression equation indicates the deviation from straightness of the line. The average RMS of all four lines is taken as an overall measure of motor disorder, and the difference in performance between the two hands serves as an index of motoric laterality. Scores on the motor disorder index were significantly positively related to clinical ratings of Parkinsonism among schizophrenic inpatients. A marginal relation was found to ratings of voluntary movement disorders, and the task was not associated with dyskinetic movements. Scores on the motor disorder measure were significantly worse for schizophrenic subjects than for staff controls. The laterality index significantly differentiated right- and left-handed subjects, but did not differentiate schizophrenic from control subjects. Maher's simple line drawing task yields objective continuous ratings of motor disorder and handedness and may be a useful tool for examining associations between motor functioning and cognition and symptomatology in schizophrenia.

Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders.

OBJECTIVE: Suicide is the single largest cause of premature death among individuals with schizophrenia. This report examines the relationship between positive or negative symptoms, illness subtype, and suicidal behavior among patients with schizophrenia and schizophrenia spectrum disorders in a long-term follow-up cohort. METHOD: Based on index admission records, patients from the Chestnut Lodge Follow-Up Study with schizophrenia (N = 187), schizoaffective disorder (N = 87), schizophreniform disorder (N = 15), and schizotypal personality disorder (N = 33) were retrospectively assessed with the Positive and Negative Syndrome Scale, classical subtype criteria, and criteria for the deficit syndrome. Completed suicide, suicide attempts, and suicidal ideation during the follow-up period (average = 19 years) were ascertained by means of interviews with patients and/or surviving relatives. RESULTS: Over the follow-up period, 40% of the patients reported suicidal ideation, 23% reported suicide attempts, and 6.4% died from suicide. Patients dead from suicide had significantly lower negative symptom severity at index admission than patients without suicidal behaviors. Two positive symptoms (suspiciousness and delusions), however, were more severe among successful suicides. The paranoid schizophrenia subtype was associated with an elevated risk (12%) and the deficit subtype was associated with a reduced risk (1.5%) of suicide. CONCLUSIONS: The impact of positive and negative symptoms on suicide risk has not been reported. These findings suggest that prominent negative symptoms, such as diminished drive, blunted affect, and social and emotional withdrawal, counter the emergence of suicidality in patients with schizophrenia spectrum disorders and that the deficit syndrome defines a group at relatively low risk for suicide. Prominent suspiciousness in the absence of negative symptoms defines a relatively high-risk group.

Clinical challenges in the psychopharmacology of schizophrenia.

Better pharmacological treatments for schizophrenia have elevated the expectations of patients and families and allow a wider range of therapeutic options for clinicians. At the same time, the treatment of schizophrenia has become more complex, and clinical decisions must often be made in the absence of unambiguous empirical guidelines. Under these circumstances, good patient care is based on clinical judgement informed by available clinical research. This issue of the Schizophrenia Bulletin reviews research in areas that represent major clinical challenges in the psychopharmacology of schizophrenia.

Determinants of medication compliance in schizophrenia: empirical and clinical findings.

Advances in psychopharmacology have produced medications with substantial efficacy in the treatment of positive and negative symptoms of schizophrenia and the prevention of relapse or symptom exacerbation after an acute episode. In the clinical setting, the individual patient's acceptance or rejection of prescribed pharmacological regimens is often the single greatest determinant of these treatments' effectiveness. For this reason, an understanding of factors that impede and promote patient collaboration with prescribed acute and maintenance treatment should inform both pharmacological and psychosocial treatment planning. We review the substantive literature on medication adherence in schizophrenia and describe a modified health belief model within which empirical findings can be understood. In addition to factors intrinsic to schizophrenia psychopathology, medication-related factors, available social support, substance abuse comorbidity, and the quality of the therapeutic alliance each affect adherence and offer potential points of intervention to improve the likelihood of collaboration. Because noncompliance as a clinical problem is multidetermined, an individualized approach to assessment and treatment, which is often best developed in the context of an ongoing physician-patient relationship, is optimal. The differential diagnosis of noncompliance should lead to interventions that target specific causal factors thought to be operative in the individual patient.

Risk factors for spontaneous dyskinesia in schizophrenia.

OBJECTIVE: We describe the prevalence, clinical correlates, and prognostic significance of spontaneous dyskinesias among 100 patients with schizophrenia from the Chestnut Lodge Follow-up Study who had never received treatment with neuroleptic agents up to and including the baseline assessment. DESIGN: Extensive case records were screened and descriptions of abnormal movements were recorded verbatim for blind rating. Neuroleptic-naive patients with and without abnormal oral-facial movements were compared across sign and symptom, schizophrenia subtype, and illness natural history variables. RESULTS: Excluding three patients with motor symptoms who had a history of neurologic illness or injury and three who had received prochlorperazine maleate therapy (Compazine), 23% of patient records documented some form of movement disorder; 15% documented oral-facial dyskinesias with sufficient detail so that their presence was considered nearly certain. Compared with patients with schizophrenia without oral-facial movements, patients with oral-facial dyskinesias were more likely to demonstrate a lower IQ score, had more negative symptoms at index admission, and were more symptomatic at follow-up an average of 23 years later. Both the classic hebephrenic schizophrenia subtype and Carpenter's Criteria for the Deficit Syndrome defined high-risk groups for spontaneous oral-facial dyskinesia. CONCLUSIONS: In previous studies, intellectual impairment and negative symptoms have been described as risk factors for neuroleptic-induced tardive dyskinesia. The present data, however, suggest that in many cases oral-facial dyskinesias in patients with intellectual impairment and negative symptoms may actually represent spontaneous movement disorders associated with hebephrenic or deficit forms of schizophrenia.

Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia.

OBJECTIVE: The authors explore the antecedents, symptom progression, and long-term outcome of patients diagnosed as having the deficit syndrome, a putative domain of psychopathology and subtype of schizophrenia defined by Carpenter's group. METHOD: Patients from the Chestnut Lodge Follow-Up Study were retrospectively rediagnosed as having deficit (N = 46) or nondeficit (N = 141) forms of schizophrenia by using the criteria of Carpenter's group. Patients with deficit and nondeficit forms of schizophrenia were compared in relation to symptom progression between first and index admission, natural history and course of illness, and long-term outcome assessed at follow-up a mean of 19 years after index admission. RESULTS: 1) Significantly fewer patients with the deficit form of schizophrenia were married before illness onset, but few other differences between patients with deficit and nondeficit schizophrenia emerged. 2) Illness onset was often insidious for patients with the deficit syndrome; once established, the illness was nearly always continuous with few remissions, and its course appeared unreactive to life events. 3) Negative symptoms among patients with the deficit syndrome were often present at illness onset and progressed in severity over the first 5 years of illness; thought disorder and bizarre behavior also increased in severity over time. 4) Once established, the deficit syndrome was highly stable. 5) The deficit syndrome was associated with a very high risk of poor outcome and long-term disability. 6) None of the patients with the deficit syndrome were known to have committed suicide. CONCLUSIONS: The data support the validity of the deficit syndrome as a subtype of schizophrenia with a relatively distinct natural history.

Sexual abuse and psychopathology.

With the recognition that sexual exploitation of children is far more common than previously thought, a substantial research effort has aimed to describe its acute and long-term effects (Kluft 1990). Most studies have been quantitative and have pursued one of two strategies: Children identified by referral from child protective services as physically victimized are concurrently assessed for psychiatric sequelae; alternatively, adults with or without various psychiatric syndromes are retrospectively asked to recall the presence or absence of traumatic childhood experiences. Descriptive in focus, the results of these research efforts have broadened our understanding of the typical constellation of symptoms experienced by childhood incest victims and have delineated the adult psychiatric diagnostic categories most associated with a history of childhood trauma.

Subtype progression and pathophysiologic deterioration in early schizophrenia.

It is important to elaborate what we know about the symptomatic, syndromal, and functional course of schizophrenia in order to test models for this illness. The sample of schizophrenic patients from the Chestnut Lodge followup study was subtyped using classical (modified DSM-III-R) criteria and deficit/nondeficit (Schedule for the Deficit Syndrome) criteria. 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. Over the same time, positive symptoms were relatively stable, but negative symptoms became significantly worse. Such changes probably reflect "deterioration" because they were associated with poorer functional outcome an average of 15 years later. These data dovetail with other reports in the literature and suggest a hierarchy of symptomatic/syndromal progression in early manifest schizophrenia that may reflect active deterioration processes at work. We suggest that any theory of schizophrenic pathophysiology must account for these patterns of symptom course.