Use of antidepressant drugs in schizophrenia.

This review surveys the therapeutic efficacy of tricyclic antidepressants and monoamine oxidase inhibitors in schizophrenic patients. In general, the use of these drugs alone was found not to be warranted in schizophrenia, except perhaps in the so-called pseudoneurotic subgroup. In most cases, combinations of antidepressants and phenothiazines were not more beneficial than phenothiazines alone. In particular, the conditions of agitated patients and patients with histories of social deviance dating back to childhood were often made worse by the addition of an antidepressant. However, when the patients who demonstrated symptoms of clinical depression other than anergia were isolated from several of these studies, it was found that they constituted a subgroup that was often benefited by use of these combinations. Favorable and unfavorable clinical response patterns are discussed, and recommendations for future research are outlined.

Predicting drug-free improvement in schizophrenic psychosis.

In a sample of 22 psychotic schizophrenic patients, eight improved substantially during a 30-day drug-free period. The drug-free improver group differed from the nonimprover group in demonstrating a later age of onset, briefer psychotic episodes, shorter hospitalizations, and better prognostic scores on the Phillips Scale, Strauss-Carpenter Modified Prognostic Scale, and the Vaillant Scale. After drug withdrawal, drug-free improvers frequently demonstrated further improvement when treated with doses of neuroleptic drugs that were substantially lower than the clinically recommended doses. The authors raise the question as to whether the drug-free improvers may represent a subgroup of schizophrenic patients who are being overtreated presently by standard neuroleptic practice.

Long-term pimozide pretreatment differentially affects behavioral responses to dextroamphetamine in schizophrenia. Further exploration of the dopamine hypothesis of schizophrenia.

In ten of 30 schizophrenic patients treated with pimozide for five weeks, 20 mg of dextroamphetamine sulfate induced an increase in psychosis. The number of patients becoming more psychotic with the dextroamphetamine challenge was not significantly different from the number who worsened after dextroamphetamine challenge when pretreated with placebo. Half of the patients who showed a psychotic response to dextroamphetamine during placebo pretreatment responded to dextroamphetamine with an increase in psychosis after pimozide treatment. Dextroamphetamine induced a worsening in patients who had improved with pimozide. The stability of the preinfusion condition is more important to the type of response to dextroamphetamine than long-term pretreatment with a dopamine receptor blocker. The activation-euphoria response to dextroamphetamine was unaffected by pimozide pretreatment, which suggests that the changes in psychosis and activation may be regulated by different mechanisms. These findings question the postulated relationship between the antipsychotic drug response and dopamine receptor blockade.

Lack of behavioral supersensitivity to d-amphetamine after pimozide withdrawal. A trial with schizophrenic patients.

The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.

Antipsychotic effects of pimozide in schizophrenia. Treatment response prediction with acute dextroamphetamine response.

Acute behavioral response to 20 mg of dextroamphetamine (intravenous) predicted fourth-week antipsychotic response to double-blind pimozide treatment. Patients whose psychotic condition improved with dextroamphetamine administration showed more antipsychotic response to pimozide therapy than those whose condition worsened or did not change. Multiple regression analysis indicated amphetamine-induced response predicted pimozide response after four weeks for fifth-week pimozide response was more accurately predicted by prepimozide psychosis ratings. Our study provides some evidence that mechanisms underlying early and late pimozide response are not necessarily identical. Because patients who did not respond to dextroamphetamine administration still improved with pimozide therapy, our data do not support the concept that schizophrenia can be divided into two groups (dopamine-sensitive or dopamine-insensitive) but, rather, that dopamine responsiveness changes over time. Clinical application is not warranted until studies with larger samples have replicated our findings.

National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments.

We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depression disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed significant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on initial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.

Prediction of early relapse after pimozide discontinuation by response to d-amphetamine during pimozide treatment.

Thirteen schizophrenic patients underwent a d-amphetamine infusion while being treated with pimozide, an antipsychotic agent and a relatively specific dopamine (DA) blocker. Six patients who showed an acute increase in psychosis with d-amphetamine relapsed within 3 months after pimozide withdrawal. Of the seven patients who did not change in psychosis with d-amphetamine, six did not relapse after pimozide discontinuation (Fisher's exact test, p less than 0.005). Retrospectively, the psychosis-inducing effects of d-amphetamine were found to be predictive of psychotic exacerbation following subsequent pimozide withdrawal. Pimozide failed to block the psychotogenic effects of d-amphetamine in six patients indicating that other mechanisms besides DA may play a role in psychotic decompensation. The d-amphetamine infusion paradigm should be studied further to determine its clinical value for identifying which schizophrenic patients are at risk for relapse after discontinuation of neuroleptic treatment.

A new concept and finding in morbid jealousy.

The authors describe an unexpected coincidental finding in three couples who sought therapy because the husband was pathologically jealous. In the course of treatment they found that during early adolescence each of these men had witnessed his mother engaged in extramarital sexual activity. The authors discuss the implications of this finding for further understanding of the etiology of the syndrome of pathological jealousy, its transactional dimensions, and possible psychotherapeutic approaches. They also present a typology of morbid jealousy that consists of excessive obsessional-delusional, and ego dysfunctional forms.

Trends in emergency psychiatry in the last two decades.

Emergency psychiatric services provide essential care. Their utilization may also be assumed to reflect the health care needs of a population. The authors observed trends in an emergency psychiatric service over a 17-year period by comparing 400 randomly selected patient visits in 1977 with date from 1960 and 1970. They found a decrease in the number of patients seeking treatment, decreased patient age and socioeconomic status, increased use by men, increased night visits, little change in diagnostic categories, and a striking increase in hospitalization since 1970. These data support the importance of assessing trends in emergency psychiatric services over time to ensure that they meet the needs of the population being served.

Conceptual and methodological issues in comparative studies of psychotherapy and pharmacotherapy, II: Nature and timing of treatment effects.

This is the second of two articles on the conceptual and methodological problems involved in comparing the effectiveness of drugs and psychotherapy in the treatment of mental disorders. Part II focuses on differences between psychotherapy and pharmacotherapy in the nature of treatment effects and related goals for treatment, differences in the time course of treatment effects, and potential sources of bias in the research setting. In designing comparative studies of psychotherapy and pharmacotherapy, investigators should address methodological choices explicitly and consider the implications for interpretation of findings.

Conceptual and methodological issues in comparative studies of psychotherapy and pharmacotherapy, I: Active ingredients and mechanisms of change.

There has recently been an increased focus on comparing the effectiveness of drugs and psychotherapy in the treatment of mental disorders. The marked differences between these two treatment forms raise many conceptual and methodological problems for the investigator. In a two-part series, the authors discuss a number of these conceptual issues and their implications for research design, implementation, and interpretation of findings. Part I focuses on differences in the active ingredients and hypothesized mechanisms of change of psychotherapy and pharmacotherapy. Issues addressed include the need for standardization of treatments, adequate delivery of treatments, and controlling for factors other than the active ingredients of each treatment.

Intrapsychic structural effects of psychiatric research.

The authors observed that many psychotic patients on a clinical/research ward incorporated various aspects of research organization into their own evolving intrapsychic structures. This process had either beneficial or deleterious clinical effects, depending on the attributes of the research and the specific mental functions to which these attributes became attached. The observations resulted in the development of a set of recommendations for maximizing the therapeutic usefulness of this phenomenon and minimizing its countertherapeutic drawbacks.

Stages of onset of schizophrenic psychosis.

On the basis of a review of the literature describing the process of schizophrenic illness, the authors conclude that schizophrenic psychosis is one stage in a process of psychological and biological breakdown that has a specific structure and a characteristic unfolding consisting of the sequential appearance of hierarchically ordered, distinguishable, and recognizable psychological states. They present on illustrative case history of a patient who was able to describe her feelings during the process of decompensation to schizophrenic psychosis and two case histories of patients whose decompensations were rated according to the authors' State of Illness Rating Scale.

Psychotherapy and pharmacotherapy: conceptual lenses.

Of the many difficulties in maintaining an integration of psychotherapeutic and pharmacotherapeutic treatment, one of the most important is "the problem of bimodal relatedness", that is, the distinction between relating to the patient as a diseased organ or object of study and as a disturbed person. The authors identify the forces that act to inappropriately emphasize one mode or the other and discuss major difficulties that arise because of failure to maintain a bimodal relatedness. In a setting of combined therapy, maintaining and safeguarding the optimal relationship of collaborative subject-subject relatedness can prevent the emergence of problem destructive to effective psychiatric treatment and research.

Poor outcome and low platelet MAO activity in chronic schizophrenia.

Platelet monoamine oxidase (MAO) activity was significantly lower among 21 chronic schizophrenic patients, 19 of whom were receiving stable doses of antipsychotic medication, than among 16 control subjects. Poor ego functioning and poor outcome were significantly correlated with low MAO activity; current dose of major tranquilizer was negatively but not significantly correlated. The degree of psychopathology, rather than presence or absence of specific symptom constellations, was the significant characteristic of patients with low enzyme levels. This finding is in accordance with those of earlier studies of schizophrenic patients as well as with recent findings in nonschizophrenic samples.

Effects of dopamine blockade on gonadotropins and testosterone in men.

The authors found that plasma luteinizing hormone (LH), prolactin, and testosterone were initially normal in nine acutely psychotic males with schizophrenia or schizo-affective disorder; follicle-stimulating hormone (FSH) was normal in eight of the nine. When patients were treated with pimozide, a relatively specific dopamine receptor blocker, there were statistically significant declines in FSH and LH, although levels remained within normal limits. Prolactin rose significantly, but testosterone did not change. The observed reductions in FSH and LH concentrations are consistent with the hypotheses that dopamine and/or prolactin play a role in gonadotropin secretion. The maintenance of normal levels of gonadotropins and testosterone, however, suggests that these patients possessed relatively normal hypothalamic-pituitary-gonadal axis function before and during a course of neuroleptic treatment.

d-Amphetamine-induced heterogeneous changes in psychotic behavior in schizophrenia.

In this placebo-paired, double-blind study, 13 of 45 schizophrenic patients showed an acute improvement in schizophrenic symptoms following d-amphetamine infusion (20 mg). The 18 patients who worsened tended to have higher CSF 3-methoxy-4-hydroxyphenylglycol levels than did those who improved. d-Amphetamine blood levels and clinical descriptors of schizophrenic subgroups did not differentiate patients who improved from those who worsened; however, patients who improved had been significantly more psychotic before the infusion. Patients who worsened had been more psychotic than those who did not change. The authors suggest that those who did not change. The authors suggest that sensitivity to dopamine stimulation in schizophrenia is state-dependent rather than trait-dependent and that the simple, undirectional hypothesis of schizophrenia needs to be reformulated.

Personality disorders and treatment outcome in the NIMH Treatment of Depression Collaborative Research Program.

The authors investigated the relationship between personality disorders and treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program, which involved 239 outpatients with major depressive disorder randomly assigned to one of four 16-week treatment conditions. Patients with personality disorders (74% of the sample) had a significantly worse outcome in social functioning than patients without personality disorders and were significantly more likely to have residual symptoms of depression. There were no significant differences in work functioning or in mean depression scores at treatment termination. Outcome was similar for patients in the different clusters of personality disorders.

Barriers to the diagnosis of depression in primary care.

Approximately 50% of people treated for depression receive treatment in primary care settings. However, studies have demonstrated that specific factors interfere with recognition of this disorder in the primary care setting and decrease the likelihood of an accurate diagnosis. Variables that relate to the patient include lack of awareness and understanding of the nature of the disease and its symptoms so that they can be accurately reported to the physician. Variability in clinical presentation and the presence of comorbid medical disorders also make detection difficult. Complaints of physical symptoms confuse the clinical picture. In addition, patients are ashamed to admit to psychological symptoms of depression and fear the stigma attached to it. Interfering factors that relate to the physician include a lack of knowledge about the disease and lack of training in its management that reduce the physician's ability to render a diagnosis and undermine confidence in the capacity to treat the illness successfully. Reluctance on the part of the physician to inquire frankly about depression also plays a role. Barriers that stem from the system include financing of care under capitated systems, other reimbursement issues, time available to care for patients, and continuity of the physician/patient relationship. A variety of tools are available to assist primary care physicians in the recognition and accurate diagnosis of depression. Use of these tools would increase the recognition and effective management of depression.

Cost of treating mental illness from a managed care perspective.

The issue of cost-effectiveness in the pharmacoeconomics of mental illness is a new concept. As methodologies for exploring this subject unfold, the most fundamental objective for health care professionals and managed care officials is to find ways in which currently available resources can be used most effectively. The managed care perspective is highly cost-based within the market it serves. In addition to cost, other factors that influence the managed care perspective are a short-term focus, segmentation of budgets, and measurable indicators of outcome, cost, and quality of care. The cost of new psychopharmacology--especially antidepressants and antipsychotics--may be many times that of traditional drugs, and concern about increased drug costs is present in many managed care organizations. Several issues must be addressed to prevent restriction of pharmacotherapeutics in managed care settings. For example, a focus on both outcomes and practice guidelines is needed to help allocate limited resources fairly. This article suggests ways in which available resources can be used more effectively to treat mental illness within the present health care system.