Alan J. Gelenberg

Prevalence of tardive dyskinesia in an outpatient population

Tardive dyskinesia (TD) is a disorder of abnormal involuntary choreothetotic movements associated with the use of neuroleptic drugs. The reported prevalence of TD among patients taking antipsychotic agents varies markedly, from 3% to 56%,1–8 accounted for, in part, by the use of different diagnostic criteria. Although most investigators use the Abnormal Involuntary Movement Scale (AIMS) to assess signs of TD, the methods of analyzing resulting data have varied widely, and there is disagreement as to the severity of abnormal movements needed to qualify for a diagnosis of TD. This divergence in severity criteria is further complicated by the heterogeneous nature of this disorder and by the effects of drugs on the appearance of the movements. For example, abnormal movements can develop temporarily when antipsychotic medication is withdrawn, but may fade over time—a syndrome more properly termed “withdrawal dyskinesias” rather than true TD. Antipsychotics can also “mask” the movements of TD. Gardos9 has coined the term “covert dyskinesia” to describe movements that only become apparent when a neuroleptic dose is lowered, but that persist over time. In other patients, TD “breaks through” a stable neuropleptic dose, but may be controlled by increasing the dose. n nOver the past 3 yr we have conducted a study of the prevalence of TD within our mental health system. This article presents data from the study and prevalence data based on four different severity criteria for the diagnosis of TD. In addition, epidemiological correlations are presented and their possible implications discussed. Finally, we will present a new scale, Targeting Abnormal Kinetic Effects (TAKE), which rates extrapyramidal signs and forms a natural companion piece to the AIMS (see Appendix 1).

Tyrosine for depression: a double-blind trial

We treated 65 outpatients with RDC major depression in a randomized, prospective, double-blind comparison of oral L-tyrosine, 100 mg/kg/day, imipramine, 2.5 mg/kg/day, or placebo for 4 weeks. Tyrosine increased and imipramine decreased 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion significantly, but there was no evidence that tyrosine had antidepressant activity. The only side effect to achieve statistical significance was greater dry mouth with imipramine. MHPG excretion and plasma amino acid concentrations failed to predict or correlate with clinical improvement.

A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness.

In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures.Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4.The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects.

Amoxapine — An Antidepressant With Some Neuroleptic Properties?: A Review of Its Chemistry, Animal Pharmacology and Toxicology, Human Pharmacology, and Clinical Efficacy

Amoxapine, a new antidepressant, exhibits both antidepressant and neuroleptic effects in laboratory animals and in humans. Evidence from human studies (extrapyramidal reactions, hyperprolactinemia, and galactorrhea), animal screening tests, and neurochemical experiments support the contention that amoxapine or a metabolite occasionally produces neuroleptic‐like effects. Amoxapines neuroleptic activity may derive from 7‐hydroxy‐amoxapine, a minor metabolite in humans, which exhibits significant dopamine receptor‐blocking activity. Evidence for an early antidepressant effect of amoxapine in the treatment of depressive illness has not been consistently demonstrated. In comparable doses (roughly twice the dose of imipramine or amitriptyline), amoxapine appears to be similar to reference antidepressants in efficacy, unwanted effects, and acute toxicity.

Amitriptyline, clovoxamine and cognitive function: a placebo-controlled comparison in depressed outpatients

No longer prescribed only for vegetative signs of depression, tricyclic antidepressants also lessen depressive cognitive distortions. Less clear is whether they ameliorate depressed patients other cognitive deficits in memory, information processing speed, and psychomotor performance. We tested the alternative hypothesis that amitriptyline, because of its anticholinergic and sedative properties, would exacerbate depressed patients cognitive disturbances. Depressed outpatients received double-blind placebo (n=15), amitriptyline (n=10), or clovoxamine fumarate (n=10), a serotonin reuptake inhibitor relatively lacking in anticholinergic properties. Depression, memory, and psychomotor performance were assessed at baseline and after 7 and 28 days of drug treatment. Depression was alleviated after all treatments, including placebo. Only amitriptyline impaired performance on tests of memory, producing a significant decrement, relative to placebo, after 4 weeks of treatment. None of the treatments adversely affected performance on psychomotor tasks. These findings add to the evidence that antidepressant drugs with high anticholinergic activity can impair memory, despite alleviation of depression.

Effects of two antidepressants on memory performance in depressed outpatients: a double-blind study

Forty outpatients with primary depression were randomly assigned on a double-blind basis to treatment with amitriptyline (a tricyclic antidepressant) or clovoxamine (a nontricyclic, experimental antidepressant). Memory and depression were assessed during a pretreatment baseline period and at the end of days 4, 7, and 28 of drug treatment. A signal detection recognition memory task and conventional memory measures (including the Benton Visual Retention, Wechsler Logical Memory, and verbal learning tests) were used to assess memory.Although both drugs led to comparable clinical improvement in depression, they affected memory performance differently. The signal detection recognition memory task detected an impairment in memory after chronic amitriptyline administration, as contrasted with an improvement in memory after chronic administration of clovoxamine. The memory impairment in the amitriptyline group and improvement in the clovoxamine group were the result of changes in sensitivity [P(A)]. No changes in response bias (BO were detected. Conventional memory tests failed to detect drug-related differences in memory between the two groups. On the Benton, errors decreased over time within both drug treatment groups, whereas correct reproductions increased within the amitriptyline group only. However, between-group differences on the Benton did not reach significance.Results from the signal detection task suggest an amitriptyline-associated memory impairment. However, this interpretation is tempered by the finding that conventional memory measures failed to detect differences in memory performance between the two groups. We discuss the limitations of traditional memory measures and the utility of a signal detection approach in studies of psychopharmacologic influences on memory.

Anticholinergic effects on memory: Benztropine versus amantadine

To evaluate anticholinergic effects on cognition and other functions, we studied 60 healthy volunteers in a double-blind crossover trial of two anti-parkinsonian agents, benztropine and amantadine. Benztropine 4 mg/day, but not amantadine 200 mg/ day, impaired free recall and perception of time, and subjects perception of their own memory impairment was significantly greater with benztropine. Side effects in general were worse with benztropine, particularly such anticholinergic effects as dry mouth and blurred vision, and benztropine decreased measured salivary flow to a significantly greater degree than amantadine. Our findings support the hypothesis that drugs that decrease cholinergic transmission impair storage of new information into long-term memory, but have little effect on retrieval from memory or on tasks involving only immediate memory. Clinically, anticholinergic agents can levy a considerable burden on memory and time perception.

Effects of lithium on the kidney

ABSTRACT— We tested kidney function in 268 patients given lithium treatment for an average period of 37.6 months and in 59 manic‐depressive patients never given lithium. No patients suffered serious renal damage during the course of our observations. Maximum concentration capacity was lower and serum creatinine concentration higher in the lithium treated patients than in the controls, but the differences did not achieve statistical significance. Females had poorer concentrating ability than males, both among the control subjects and during lithium treatment. Concomitant antipsychotic drug therapy may affect concentrating ability and possibly glomerular function adversely.

Tyrosine for depression.

The catecholamine hypothesis of affective disorders postulates that depression reflects inadequate norepinephrine activity at unspecified brain centers that regulate mood. In light of experimental data showing that the oral administration of tyrosine, precursor of the catecholamine series of neurotransmitters, can increase brain norepinephrine concentrations and activity, we have conducted preliminary trials of tyrosine in depressed outpatients. Initial results are encouraging, and we are now conducting a double-blind, parallel-group trial comparing tyrosine to the tricyclic antidepressant imipramine and to placebo in non-bipolar outpatients with major depression.

Chemistry, pharmacology, pharmacokinetics, adverse effects, and efficacy of the antidepressant maprotiline hydrochloride.

Maprotiline, a tetracyclic antidepressant with sedative properties, exhibits strong inhibitory effects on norepinephrine uptake across nerve cell membranes but interferes relatively little with serotoninergic mechanisms. The biological half‐life of unchanged maprotiline in blood averages 43 hours. Though several studies suggest a more rapid onset of antidepressant effects with maprotiline than with amitriptyline or imipramine, this issue remains unresolved.