Amphetamine effects in man: paradoxical drowsiness and lowered electrical brain acitivity (CNV).

Thirteen of 20 normal adults given 10 milligrams of dextroamphetamine exhibited paradoxical drowsiness accompanied by lowered electrical brain activity (contingent negative variation, or CNV) in the first hour post-drug. During this period, seven subjects showed behavioral alertness and increased CNV amplitude. Both groups of subjects showed heightened alertness 2 and 3 hours post-drug. Amphetamine is not a simple stimulant of the central nervous system but can also act as a depressant.

The use of psychostimulants in general psychiatry. A reconsideration.

A half century after the introduction of amphetamine sulfate (benzedrine), there remains active interest in the use of the major psychostimulants (ie, methylphenidate hydrochloride and pemoline) for the treatment of psychiatric disorders. In the absence of any recent review of the literature on the clinical uses of psychostimulants, we assessed the existing data on the adult psychiatric indications for these agents. Generally, the existing studies are old and inadequate. However, there is some evidence to support the judicious use of psychostimulants in selected clinical instances of several adult psychiatric syndromes.

Benzodiazepines in depressive disorders.

Some investigators have found benzodiazepines effective in the treatment of anxious depression and thus have argued that benzodiazepines were "antidepressants." We reviewed the literature on benzodiazepines in depressive disorders. Comparative studies indicate they are less effective than standard antidepressants in the treatment of several types of depressive illnesses. Although they display definite anxiolytic properties and may elevate mood, they exert limited effect on the core symptoms of endogenous depression. An argument is made that benzodiazepines are primarily anxiolytic rather than antidepressant.

The assessment of tardive dyskinesia.

Available assessment methods for tardive dyskinesia were reviewed under three headings: instrumentation, frequency counts, and rating scales. The more objective methods have better reliability but less certain validity, while for the clinical assessment techniques the converse tends to be true. The optimat assessment method for a given study depends on the research question asked. For most studies, the combination of one of the objective techniques with a rating method may be ideal. Research on prevalence and etiological factors would benefit from one of the multi-item rating scales, while in treatment studies a global scale may be necessary. Videotapes are invaluable for educational purposes and for training raters.

Extrapyramidal side effects in chlorpromazine recipients: emergence according to benztropine prophylaxis.

The frequency of extrapyramidal symptoms (EPS) attributed to chlorpromazine among 86 patients who received benztropine for the prevention of EPS (9.3%) was similar to that of the 568 patients who received chlorpromazine alone (10.6%). The data in this small sample indicated that the prophylactic use of benztropine had no effect in reducing the rate of EPS.

Drug use and life-style among college undergraduates. Nine years later.

A questionnaire study of drug use and life-style among college seniors, previously performed in 1969, was repeated at the same college in 1978 with identical methods. Moderate increases in marijuana use were found; cocaine use had increased dramatically; most other drug use changed only slightly. Differences between users and nonusers, already modest in 1969, had narrowed further by 1978: users and nonusers were indistinguishable on grades, athletics, other college activities, career plans, and subjective alienation. Only heterosexual activity and visits to a psychiatrist still distinguish users from nonusers.

Maprotiline treatment in depression. A perspective on seizures.

Eleven McLean Hospital (Belmont, Mass) depressed patients who experienced seizures while receiving maprotiline hydrochloride are presented, as are data on 87 cases reported to the manufacturer (Ciba-Geigy). Most seizures occurred at high dosages, sometimes after many weeks at a stable dose, but neither rapid dosage escalation nor high drug plasma levels seemed related to seizure occurrence. Our experience suggests that a long-acting metabolite might be responsible for seizures. Ten of the 11 McLean Hospital seizures occurred in patients receiving dosages outside of the since-revised current dosage guidelines, as did 60% of the seizures reported to the company. Data in this study suggest that reductions in maximum dosage of maprotiline prescribed after the initial six weeks of treatment could result in a further decrease in risk of seizures beyond that obtained from previous alterations in regimens.

Hypotension due to chlorpromazine. Relation to cigarette smoking, blood pressure, and dosage.

The frequency of hypotension attributed to orally administered chlorpromazine hydrochloride was compared among 187 nonsmokers, 223 "light" smokers, 87 "intermediate" smokers, and 18 "heavy" smokers. Hypotension attributed to the drug occurred in10%, 8%, 5% and 0%, respectively. Other factors found to be independently related to hypotension were high diastolic blood pressure on admission and high dosage of chlorpromazine. The results suggest that smoking status, dosage, and blood pressure must be evaluated in order to estimate the likelihood that a patient may become hypotensive after receiving chlorpromazine.

Toward a biochemical classification of depressive disorders. I. Differences in urinary excretion of MHPG and other catecholamine metabolites in clinically defined subtypes of depressions.

The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and other catecholamine metabolites was measured in a series of 63 patients with various clinically defined subtypes of depressive disorders. MHPG excretion was significantly lower in patients with bipolar manic-depressive depressions and schizo-affective depressions than in patients with unipolar nonendogenous depressions. Patients with schizophrenia-related depressions also excreted reduced levels of MHPG when compared with patients with unipolar nonendogenous depressions. Moreover, levels of urinary epinephrine and metanephrine were significantly lower in patients with schizophrenia-related depressions. These data, coupled with our recent finding that patients with schizophrenia-related depressions had significantly higher levels of platelet monoamine oxidase activity than control subjects of patients with unipolar endogenous depressions, suggest that we can discriminate three biochemically discrete subgroups of depressive disorders corresponding to the following clinically defined subtypes: (1) the bipolar manic-depressive depressions plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions; and (3) the schizophrenia-related depressions.

Toward a biochemical classification of depressive disorders. II. Application of multivariate discriminant function analysis to data on urinary catecholamines and metabolites.

The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders.

Toward a biochemical classification of depressive disorders. X. Urinary catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders.

Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.

Anticholinergic challenge and neuroleptic withdrawal. Changes in dyskinesia and symptom measures.

Benztropine mesylate (intravenous [IV] and oral) challenge was compared with brief neuroleptic withdrawal on dyskinesia ratings and symptom measures. Thirty-six neuroleptic-treated patients underwent a placebo-controlled acute IV challenge with 2 mg benztropine and a placebo-controlled two-week trial of oral benztropine mesylate (2 mg three times a day), followed by a double-blind placebo-controlled neuroleptic withdrawal involving four weeks of dose tapering and six weeks of placebo treatment. Benztropine given IV had no significant effect. Orally administered benztropine, however, led to statistically significant increases in dyskinesia and dysphoric mood. The brief neuroleptic withdrawal significantly increased dyskinesia scores and dysphoria and resulted in early termination of therapy in 12 of 36 patients (33%) due to symptom exacerbation. There was a striking absence of correlation between dyskinesia change measures brought about by benztropine and changes following neuroleptic withdrawal. Therefore anticholinergic challenge does not appear to be a fruitful procedure for identifying patients with covert dyskinesia.

Prevalence and severity of akathisia in patients on clozapine.

The atypical antipsychotic clozapine is reported to have unique therapeutic effects and to produce minimal extrapyramidal side effects. However, in a blind survey, akathisia was observed to be similar in prevalence and severity in patients treated with clozapine and those receiving standard neuroleptic antipsychotic drugs. In addition, as with standard antipsychotic drugs, the presence of akathisia in patients receiving clozapine was associated with a worse overall clinical outcome. The results suggest that akathisia may be a common side effect of all antipsychotic drugs, that akathisia may be produced by a mechanism distinct from other locomotor effects of these medications, and that patients receiving clozapine, like patients receiving standard antipsychotic drugs, should be monitored for akathisia.

Clozapine in the treatment of dysphoric mania.

Seven patients with bipolar disorder, characterized by dysphoric mania with psychotic features and chronic disability, refractory to standard treatments and anticonvulsants, all showed marked symptomatic and functional improvement when given the atypical antipsychotic clozapine. During follow-up over 3-5 years, most of the patients sustained substantial gains in psychosocial function; and of the six patients remaining on clozapine, no further hospitalizations were needed. This remarkable improvement in a severely ill group of patients suggests that clozapine may have utility in the treatment of bipolar disorder as well as schizophrenia.

Rapid antidepressant response to alprazolam in depressed patients with high catecholamine output and heterologous desensitization of platelet adenylate cyclase.

The present study examined the relationship between 24-hr urinary catecholamine (norepinephrine and epinephrine) output and measures of platelet adenylate cyclase (AC) activity in depressed patients (n = 17) and control subjects (n = 10). In both groups, significant inverse correlations were observed when 24-hr urinary catecholamine levels were examined in relation to measures of both receptor-mediated (prostaglandin D2 and alpha 2-adrenergic) and postreceptor-mediated (NaF) platelet AC enzyme activities, suggesting that circulating catecholamines may regulate platelet AC by heterologous (agonist-nonspecific) desensitization of the AC enzyme complex. Depressed patients who had favorable antidepressant responses to alprazolam had significantly higher pretreatment urinary catecholamine output and lower receptor-mediated platelet AC enzyme activities than control subjects, whereas the nonresponders did not. After 8 days of treatment with alprazolam, urinary catecholamine levels declined significantly. In responders, receptor-mediated measures of platelet AC activity increased significantly by day 8 to values comparable to those in control subjects; but similar changes were not observed in nonresponders. Prior to treatment, responders showed a strict linear relationship between receptor-mediated (prostaglandin D2) and postreceptor-mediated (NaF) stimulation of platelet AC activity through the stimulatory guanine nucleotide regulatory protein (Ns), whereas nonresponders did not. This suggests the presence of two distinct coupling interactions between platelet prostaglandin D2 receptors and the stimulatory guanine nucleotide regulatory protein in responders and nonresponders to the antidepressant effects of alprazolam prior to treatment. The authors propose that catecholamines, possibly acting through prostaglandins, may regulate platelet AC enzyme activity by heterologous desensitization occurring through postreceptor mechanisms.

Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

Amitriptyline selectively disrupts verbal recall from secondary memory of the normal aged.

Amitriptyline, a frequently prescribed tricyclic antidepressant, is reported to produce an age-related impairment in anterograde memory. However, the locus of this adverse effect has never been described within the context of contemporary learning and memory theory. Fifteen normal elderly subjects were treated with 50 mg amitriptyline and placebo in a cross-over study. A computerized stage analysis of memory revealed that sensory and primary memory were not affected while verbal recall from secondary memory was markedly disrupted by amitriptyline. Further examination of secondary memory revealed that amitriptyline impaired recall, but not recognition. The profile of anterograde memory impairments observed with amitriptyline is similar to that previously reported for the antimuscarinic, scopolamine. Since amitriptyline at the dose employed in this study would be expected to exert marked central antimuscarinic effects, it appears likely that it is the pharmacologic blockade of central muscarinic receptors in the aged that results in the selective disruption of verbal recall in secondary memory.

Assessing the subjective effects of stimulants in casual users. A methodology and preliminary results.

In order to assess the subjective effects of nefopam, a new non-opiate analgesic, a study was designed using highly educated, young, middle-to-upper class subjects in a naturalistic setting. Results suggest that the design is capable of differentiating variations in subjective drug effects. On a number of measures, 10 mg of d-amphetamine, a modest dosage, could be distinguished from placebo, showing changes in the direction expected for stimulant drugs. Nefopam (90 mg), on the other hand, showed few differences from placebo or caffeine (300 mg). Nefopam appeared mildly dysphoric, rather than stimulant, in subjective effects.

Research barriers in psychopharmacology.

The author discusses barriers to psychopahrmacological research, including attacks by vocal human rights groups, regulation by local review boards, and Department of Health, Education, and Welfare restrictions. He suggests that those patients least able to give informed consent are most in need of the benefits of research on new drugs.

Maintenance antipsychotic therapy: is the cure worse than the disease?

The serious long-term complications of maintenance antipsychotic therapy led the authors to undertake a critical review of outpatient withdrawal studies. Key findings included the following: 1) for a least 40% of outpatient schizophrenics, drugs seem to be essential for survival in the community; 2) the majority of patients who relapse after drug withdrawal recompensate fairly rapidly upon reinstitution of antipsychotic drug therapy; 3) placebo survivors seem to function as well as drug survivors--thus the benefit of maintenance drug therapy appears to be prevention of relapse; and 4) some cases of early relapse after drug withdrawal may be due to dyskinesia rather than psychotic decompensation. The authors urge clinicians to evaluate each patient on maintenance antipsychotic therapy in terms of feasibility of drug withdrawal and offer practical guidelines for withdrawal and subsequent management.