Search

The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis., Competing Interests: Prof. Leucht has received honoraria as an adviser, for lectures, and/or for educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharp and Dohme, Mitsubishi, Neurotorium, Novo Nordisk, Otsuka, Recordati, Roche, Rovi, Sanofi-Aventis, and Teva. Dr. Priller has a patent on erythropoietin variants and is a member of the SINAPPS2 Trial Steering Committee. Dr. Davis reports no financial relationships with commercial interests.

Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system., Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group., Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine., Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

Objective: The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses., Methods: A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses., Results: Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice., Conclusions: In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Objective: The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population., Method: The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview-Revised. The authors then combined data from previous studies (N=524) for final analyses., Results: A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, NBPF1 and NBPF14 (R 2 =6.2%). Associations were preferentially found in multiplex versus simplex families., Conclusions: The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.

Objective: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences., Method: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression., Results: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time., Conclusions: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.

Objective: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia., Method: Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis., Results: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group., Conclusions: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

Objective: Whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia is a matter of heated debate. The authors conducted a systematic review and meta-analysis of blinded studies comparing second-generation antipsychotics head-to-head., Method: Searches of the Cochrane Schizophrenia Group's register (May 2007) and MEDLINE (September 2007) were conducted for randomized, blinded studies comparing two or more of nine second-generation antipsychotics in the treatment of schizophrenia. All data were extracted by at least three reviewers independently. The primary outcome measure was change in total score on the Positive and Negative Syndrome Scale; secondary outcome measures were positive and negative symptom subscores and rate of dropout due to inefficacy. The results were combined in a meta-analysis. Various sensitivity analyses and metaregressions were used to examine bias., Results: The analysis included 78 studies with 167 relevant arms and 13,558 participants. Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Risperidone was more efficacious than quetiapine and ziprasidone. Clozapine proved superior to zotepine and, in doses >400 mg/day, to risperidone. These differences were due to improvement in positive symptoms rather than negative symptoms. The results were rather robust with regard to the effects of industry sponsorship, study quality, dosages, and trial duration., Conclusions: The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in side effects and cost.

Objective: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings., Method: A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached., Results: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations., Conclusions: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Objective: Maintenance medication is critical in the prevention of psychotic relapse and rehospitalization among patients with schizophrenia. Given potential adverse effects, identification of the minimum effective dose is clinically important., Method: A multicenter, double-blind study was conducted to determine rates of symptomatic exacerbation and adverse effects in 105 outpatients with schizophrenia randomly assigned to four different fixed doses of haloperidol decanoate and treated for 1 year or until relapse. The doses used were 25, 50, 100, and 200 mg given intramuscularly once per month., Results: Rates of symptomatic exacerbation were 15% in the 200-mg group, 23% with 100 mg, 25% with 50 mg, and 60% with 25 mg. No significant differences in outcome were found between the groups treated with 200, 100, and 50 mg. Among the patients who completed the trial with no symptomatic exacerbation, there were no differences between dose groups on measures of psychopathology at the final rating point., Conclusions: The results of this study suggest that the 200-mg/month dose of haloperidol decanoate is associated with the lowest rate of symptomatic exacerbation (15%) with minimal increased risk of adverse effects or subjective discomfort in comparison to 100 or 50 mg. At the same time, the rates of worsening with 100 mg (23%) and 50 mg (25%) were not significantly greater than that seen with 200 mg. These results provide some guidance as to effective dose ranges of haloperidol decanoate.

Objective: Recent reports have criticized the design of antidepressant studies and have questioned their validity. These critics have concluded that antidepressants are no better than placebo treatment and that their illusory superiority depends on methodologically flawed studies and biased clinical evaluations. It has been suggested that the blind in randomized trials is penetrable-since clinician's guesses exceed chance-and that only active placebo can appropriately camouflage the difference between drug and placebo response. Furthermore, evidence has been cited to suggest that psychotherapy is as effective as antidepressants in both the acute and maintenance treatment of depression. These positions are often accepted as valid and have been broadly discussed in both the lay press and scientific literature. The purpose of this review is to reassess the cited data that support these assertions., Method: The authors examined the specific studies that were cited in these reports, evaluated their methodology, and conducted aggregate analyses., Results: Analyses of the original sources failed to substantiate 1) that standard antidepressants are no more effective than placebo, 2) that active placebo offers an advantage over inactive placebo, or 3) that substantial evidence of a medication bias is suggested by raters' treatment guesses exceeding chance. The authors also note that some researchers have suggested that the interpretation of psychotherapy trials can be complicated by "allegiance effects.", Conclusions: The issue of bias or allegiance effects for both antidepressant and psychotherapy research is real. Investigators of all orientations must guard against potential bias. However, studies cited as supporting the questionable validity of antidepressant trials fail upon closer examination to support assertions that these trials are invalid.

Objective: This study investigated the efficacy of verapamil in acute mania., Method: The study was a 3-week double-blind, random-assignment, parallel-group, placebo-controlled inpatient trial of verapamil for patients with acute mania. Of the 32 study patients, 15 were given placebo and 17 were given verapamil., Results: Mean absolute change scores on the Mania Rating Scale at endpoint, with baseline scores as the covariates, did not differ between the verapamil and placebo groups. There were no significant differences between the two groups in age, sex, and presence of psychosis., Conclusions: The investigators found no benefit of verapamil over placebo in treating acute mania.

Objective: Although hypersecretion of cortisol has frequently been reported in psychotic depression, the findings have been mixed. The authors performed a meta-analysis of the existing studies to determine the significance of differences in nonsuppression of cortisol across studies., Method: Fourteen studies that compared dexamethasone suppression test (DST) results in psychotic and nonpsychotic patients were examined, and a Mantel-Haenszel meta-analysis was performed. For comparison purposes, 19 studies of the DST with respect to melancholic/nonmelancholic and inpatient/outpatient distinctions were similarly reviewed., Results: This analysis indicated a highly significant probability that a greater rate of cortisol nonsuppression occurs in psychotic depression. The nonsuppression rate was substantially higher in patients with psychotic depression (64%) than in nonpsychotic patients (41%). In the 19 studies of melancholia, nonsuppression was less frequent (36%), and when inpatient/outpatient status was controlled, melancholic depression was not significantly associated with nonsuppression. In nonmelancholic outpatients with major depression, the nonsuppression rate was low (12%)., Conclusions: Among patients with major depression, psychotic depression is the subtype that is most closely associated with nonsuppression of cortisol on the DST. Hypercortisolemia is usually present in psychotic depression and may be important in understanding the pathophysiology of this syndrome.

Objective: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships., Method: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia., Results: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml., Conclusions: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Objective: The aim of this study was to compare levels of CSF somatostatin (somatotropin release-inhibiting factor) in drug-free patients with different major psychiatric disorders., Method: CSF somatostatin concentrations were measured in 66 drug-free inpatients with Research Diagnostic Criteria diagnoses of schizophrenia, major depressive disorder, manic disorder, or schizoaffective disorder., Results: In comparison with both the patients with schizophrenia and the patients with schizoaffective disorder, the manic patients had markedly elevated CSF somatostatin concentrations. The depressed patients had significantly higher levels than the schizophrenic patients., Conclusions: Mania is associated with relatively higher CSF somatostatin concentrations.

Objective: This study examined associations between four types of major psychopathology--schizophrenia, schizoaffective disorder, and bipolar and unipolar affective disorders--and history of violent crime. The effects of demographic variables, substance abuse, psychosis, and paranoia on history of violent crime were also determined., Methods: Diagnostic assessments using the Schedule for Affective Disorders and Schizophrenia and Research Diagnostic Criteria identified 172 state hospital inpatients with the four diagnoses of interest, as well as those with co-existing substance use disorders. Based on arrest records, patients were categorized according to the most violent crime for which they had been arrested., Results: Patients with schizoaffective disorder were significantly more likely than those in the other diagnostic groups to have been arrested for a violent crime. Similar results were found for psychotic patients compared with nonpsychotic patients, patients who had paranoid schizophrenia compared with patients who had schizophrenia without paranoid features, and patients who had co-existing substance abuse compared with those with no history of substance abuse. Patients from racial minority groups and male patients were also more likely than white patients and female patients to have been arrested for a violent crime., Conclusions: Demographic features, a diagnosis of schizoaffective disorder, psychosis, paranoid symptoms, and substance abuse may all be associated with violent behavior.

Objective: Abnormalities in the serotonergic system have been implicated in suicidal behavior. Higher numbers of serotonin-2 (5-HT2) receptors have been reported in the post-mortem brain of suicide victims. In order to further examine the role of 5-HT2A receptors in suicidal behavior, the authors studied 5-HT2A receptors in platelets of suicidal and nonsuicidal patients as well as normal comparison subjects., Method: 5-HT2A receptor levels were determined by using [125I]LSD as a radioligand in platelets obtained from hospitalized psychiatric patients (N = 131) and nonhospitalized normal comparison subjects (N = 40) during a drug-free baseline period. Patients were diagnosed according to DSM-III-R criteria, and suicidal behavior was identified by using the Hamilton Depression Rating Scale., Results: The mean maximum number of binding sites (Bmax) of platelet 5-HT2A receptors for all suicidal patients was significantly higher than for nonsuicidal patients or normal comparison subjects. This significant difference remained when subgroups of suicidal patients with depression, schizophrenia, schizoaffective disorder, or bipolar illness were compared to the other two subject groups. The higher number of platelet 5-HT2A receptors in suicidal patients was independent of diagnosis. While there was no significant difference in Bmax between patients with serious suicidal ideation and those who made suicidal attempts, both groups had significantly higher Bmax than normal comparison subjects., Conclusions: The observed higher number of platelet 5-HT2A receptors in suicidal patients is independent of diagnosis and appears to be associated with both the brain and the platelets of suicidal patients. These results thus suggest the potential usefulness of platelet 5-HT2A receptors as a biological marker for identifying suicide-prone patients.

Objective: A subpopulation of chronically mentally ill patients, sometimes referred to as "revolving door" patients, are frequently readmitted to psychiatric units. This study examined the relationships among demographic features, diagnostic characteristics, and frequency of hospitalization of patients from four state hospitals., Method: Two semistructured, standardized instruments, the Schedule for Affective Disorders and Schizophrenia and a life events history, were administered to 135 inpatients who met the Research Diagnostic Criteria for schizophrenia (N = 56), schizoaffective disorder (N = 33), unipolar major depressive disorder (N = 23), and bipolar disorder (N = 23). Criminal history was assessed by arrest records. The main outcome measure was the number of hospitalizations., Results: Chi-square and trend test analyses indicated that substance abuse and noncompliance with medication regimens were significantly associated with higher frequencies of hospitalization. A multiple regression model, which included alcohol/drug problems, medication noncompliance, and six sociodemographic and diagnostic variables (age, gender, race, marital status, years of education, and diagnosis) accounted for a significant proportion of the ability to predict frequency of hospitalization. Half of this predictability was due to the relationship of substance abuse and medication noncompliance with number of hospitalizations., Conclusions: Alcohol/drug problems and noncompliance with medication were the most important factors related to frequency of hospitalization. Preventing these behaviors through patient education may reduce rehospitalization rates.

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.

Hospitalized patients were divided into nonpsychotic severely depressed (N = 53), nonpsychotic moderately depressed (N = 54), and psychotic depressed (N = 25) groups and treated with either imipramine or amitriptyline, up to 250 mg/day, for 4 weeks. Good response occurred in 39% of the 38 severely depressed, 67% of the 49 moderately depressed, and 32% of the 19 psychotic depressed patients who completed treatment. The response of the patients with nonpsychotic severe depression did not differ significantly from the response of those with psychotic depression, and both groups fared worse than the group with nonpsychotic moderate depression.

The authors measured the urinary metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in 21 hyperactive boys and 12 matched healthy boys. The hyperactive boys excreted lower amounts of MHPG than control boys. Hyperactive drug responders excreted lower amounts of HVA than control boys and hyperactive nonresponders. Drug responders with normal MHPG excreted low amounts of HVA and those with normal HVA excreted low amounts of MHPG. d-Amphetamine decreased MHPG in all drug responders and HVA in drug responders with normal HVA levels, although it tended to increase HVA in those with low HVA levels. The authors discuss their data in terms of the possible involvement of norepinephrine and dopamine in the etiology of hyperactivity in children.

Hospital psychiatry has evolved from long-term "treatment" programs that were primarily custodial to the successful pharmacological treatment of acute psychotic episodes. Unfortunately, many patients still return to the hospital with relapses. This so-called revolving door syndrome draws attention to the critical importance of preventing as well as treating acute episodes. In the first part of this overview, the author reviews the clinical literature on prophylactic treatment of schizophrenia with maintenance antipsychotic drugs. The second part will review the literature on prophylactic treatment of affective disorders with lithium and tricyclics. In the opinion of the author these drugs provide the potential for truly preventive psychiatry.

The activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often high in depressive illness. The authors studied 132 depressed patients and 80 healthy control subjects. They report a significant direct association between HPA axis activity and adrenomedullary epinephrine secretion in depressed patients. They also found that depressed patients with high HPA activity tend to have lower CSF levels of 5-hydroxyindoleacetic acid, a serotonin metabolite, and modestly lower levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of epinephrine and norepinephrine, than patients with normal HPA activity. These findings provide potentially important leads for understanding interactions of biogenic amine systems with HPA axis function.

In a study of beta-adrenergic receptor sensitivity, the authors determined the response of cyclic AMP synthesis to in vitro addition of norepinephrine (NE) and isoproterenol (IP) in leukocytes of patients with affective illness and schizophrenia and of normal controls. IP-stimulated increase in 3H-cyclic AMP synthesis in depressed patients was significantly lower than in normal subjects and schizophrenic patients. These results suggest that beta-adrenergic receptor sensitivity is reduced in depressive illness.

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.

In the context of the dopamine hypothesis of schizophrenia, the authors examined postsynaptic dopamine (DA) receptor sensitivity in schizophrenic patients by means of a neuroendocrine strategy using the DA receptor agonist apomorphine and growth hormone (GH) release as the measurable postsynaptic event. The activity of platelet adenylate cyclase, an enzyme intimately associated with catecholamine receptor activity, was also studied following stimulation by prostaglandin E1 (PGE1). Patients diagnosed as having acute schizophrenia had significantly higher GH responses and adenylate cyclase activity than normal control subjects and patients diagnosed as having chronic schizophrenia. Chronic schizophrenic patients with and without tardive dyskinesia showed GH responses slightly lower than but not significantly different from those of control groups.

The authors conducted a study in which schizophrenic-like behavioral disturbances were induced in members of a macaque social colony by the chronic administration of d-amphetamine. Animals given the drug showed hypervigilance, hyperactivity, fragmented and repetitive behaviors, and progressive social withdrawal as well as the development of solitary stereotypies. The syndrome was dissected pharmacologically with alpha-methyl-para-tyrosine, chlorpromazine, pimozide, and haloperidol. Based on the behavioral findings and the known mechanisms of action of these drugs, the authors conclude that the major elements of the psychotic-like behavior induced by d-amphetamine were mediated by dopamine systems.

The authors trace three phases in the course of anorexia nervosa and compare its physical and psychological symptoms with those of starvation. Phase I, which may occur months or years before the illness, usually includes precipitating events that result in loss of self-esteem and increased self-consciousness about physical appearance. During phase II patients develop the "anorectic attitude," an unreasonable fear of eating, and show pride in their ability to lose weight. By phase III patients are forced by the severity of starvation symptoms to admit that they are ill. Although many of the physical symptoms of starvation and anorexia nervosa are similar, anorectic patients, in contrast to victims of starvation, show high initiative, the ability to suppress hunger, restless hyperactivity, and body image distortion.

The authors studied 64 depressed patients who were receiving a vanillylmandelic acid (VMA)-free diet and underwent a washout period (mean, 24 days) before treatment. During the washout period, a mean of 2.5 multiple 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) samples per patient were collected. Thirty-four patients were then treated with a "noradrenergic" antidepressant only (e.g., imipramine), and seven were treated with a "serotonergic" antidepressant only (e.g., amitriptyline). Twelve patients received combined drug treatment and 11 others spontaneously remitted. Response to treatment was rated on a clinical global evaluation scale from 1 (little or no response) to 7 (maximum response). No relationship was found between response to treatment, type of treatment, and the average pretreatment 24-hour urinary MHPG level. The authors thus failed to confirm the hypothesis that a low MHPG level predicts response to antidepressant treatment.

The in vivo RBC/plasma Li+ ratio is determined by the equilibrium between Li+ influx (ouabain-sensitive Na+-K+ pump and ouabain-insensitive leakage pathways) and Li+ efflux (phloretin-sensitive Li+-Na+ counterflow). A study of RBC Li+ transport via these pathways showed that a deficiency of Li+-Na+ counterflow was responsible for the high in vivo ratio (1:1) observed in a manic patient. This defect was related to an alteration in the membrane Na+ exchange system and was under genetic control. The level of counterflow before lithium therapy was an excellent predictor (r = .88) of the in vivo Li+ ratio and was deficient in approximately one-fourth of manic-depressive patients but not in controls, schizophrenics, or unipolar depressed patients.

The authors analyzed several rigorously controlled studies that compared the efficacy of ECT with that of simulated ECT, placebo, and antidepressants. The data from these studies were combined statistically (with the Mantel-Haenszel method for the combination of fourfold tables), showing ECT's clear superiority over all these other forms of treatment for severe depression. The authors similarly analyzed the data from several studies comparing the efficacy of unilateral nondominant ECT with that of bilateral ECT and found no significant difference in their efficacy.

This study examined relationships between depressive subtypes, clinical-behavioral characteristics, and hypothalamic-pituitary-adrenocortical (HPA) function in 132 hospitalized depressed patients. There were significant positive correlations between several pre- and postdexamethasone plasma cortisol measures and anxiety, psychomotor disturbance, distressed expression, and sleep disturbance. Few significant relationships were seen between illness severity and HPA function. Virtually no endocrine differences were seen between endogenous and nonendogenous subtypes or between psychotic and nonpsychotic subtypes. These results and the previous literature suggest a profile of depressed patients with HPA overactivation; they are likely to be anxious, to have sleep and psychomotor disturbances, to have lost weight in the current episode, and to be older.

The authors used a combined behavioral and neuroendocrinological strategy to investigate the relevance of abnormalities in the brain dopaminergic systems to the pathophysiology of tardive dyskinesia by assessing the effects of apomorphine, a directly acting dopamine agonist, and d-amphetamine, an indirectly acting dopamine agonist, in patients with tardive dyskinesia. Administration of I.V. d-amphetamine increased dyskinetic movements in most patients with tardive dyskinesia, a finding consistent with the dopaminergic hypothesis. Contrary to predictions based on animal models, apomorphine did not increase dyskinetic movements in these patients but instead substantially reduced dyskinesia in some patients. Patients with tardive dyskinesia did not have a greater drop in serum prolactin or a greater rise in serum growth hormone after apomorphine than normal or chronic schizophrenic subjects without tardive dyskinesia.

The authors conducted placebo-controlled double-blind studies of physostigmine, choline, and deanol in 12 patients with tardive dyskinesia. Physostigmine and choline both had a positive therapeutic effect on tardive dyskinesia, but the authors note that interpretation of these results is not entirely clear because they found that the sedation effect of physostigmine may nonspecifically reduce the intensity of tardive dyskinesia symptoms. Deanol was not found to be effective in this group of patients; the authors suggest that this drug should not be assumed to be generally effective unless effectiveness is verified by a large placebo-controlled double-blind study.

The authors studied neuroleptic concentration-therapeutic response curves for butaperazine (BPZ), a piperazine phenothiazine, in 10 schizophrenic patients during the first 12 days of treatment. BPZ bound to red blood cells (RBC) was more strongly correlated with therapeutic response than was plasma BPZ. RBC BPZ concentrations could be used to define a "therapeutic window", an optimun concentration for therapeutic response, above and below which favorable response diminishes. The authors emphasize the preliminary nature of the data but suggest that levels of RBC-bound neuroleptic may provide an important guide for dosage regulation in schizophrenic patients.

In a double-blind, placebo-controlled, crossover study of the effect of lecithin on memory test performance, nine normal paid volunteers (age range = 22-55 years) took single oral doses of placebo and lecithin (20 g) 5 hours before cognitive testing. Lecithin raised plasma choline levels during the test session to nearly double the placebo levels, but a categorized serial learning task, a word recognition task, a paired associates learning task, and a test of retrieval by category demonstrated no significant change in memory performance. Lecithin did not selectively enhance memory for low-imagery words. Lecithin also had no effect on psychomotor speed.

The authors examined the effect of diets with low and high monoamine content on the 24-hour urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and creatinine in eight healthy preadolescent boys. The subjects were admitted to a clinical research center and were placed on a diet low in monoamines--the vanillylmandelic acid (VMA)-exclusion diet--for 5 consecutive days. They were switched on the 6th day to a diet rich in monoamines, and urine specimens were collected for 4 more consecutive days. There were no differences in MHPG or creatinine excretion between the urine taken on the low and high monoamine diet days.

In the first part of this overview the author reviewed the clinical literature on prophylactic treatment of schizophrenia with maintenance antipsychotic drugs. In this second part he reviews the literature on maintenance treatment of affective disorders with lithium and tricyclics. He concludes that the growing realization that maintenance treatment is necessary to prevent recurrences of both mania and depression in bipolar disease and depression in unipolar disease is one of the most important advances in psychiatric therapeutics. The effectiveness of maintenance treatment provides the potential for a truly preventive approach to the treatment of affective disorders.

Relationships between pretreatment neurotransmitter metabolite levels and response to imipramine and amitriptyline were studied in 104 depressed patients. Normal values for urinary norepinephrine and low values for urinary MHPG were associated with greater incidence of drug response in bipolar, but not unipolar, patients. For unipolar, but not bipolar, patients low CSF 5-HIAA and high urinary metanephrine values were associated with a greater incidence of drug response. These data indicate that the pretreatment functional state of catecholamine and serotonin systems is associated with type of response to drug treatment. The authors present hypotheses about the association of alterations in serotonin and norepinephrine systems and definable subtypes of depression.

The authors studied 52 depressed inpatients to examine treatment response to phenelzine, a monoamine oxidase (MAO) inhibitor. All patients were classified into one of three RDC categories (definitely psychotic, probably psychotic, and nonpsychotic). For the entire sample, the mean platelet MAO inhibition level achieved with phenelzine was greater than 80%. Response to treatment was determined by independent clinical assessment and by the change in rating scores from baseline; 68% of the nonpsychotic, 43% of the probably psychotic, and 21% of the definitely psychotic patients were classified as responders. This differential response rate is similar to that reported in the literature for tricyclic antidepressants.