Cigarette craving, smoking withdrawal, and clonidine.

Clonidine, an alpha-2-adrenergic agonist, significantly reduces opiate withdrawal. Fifteen heavy smokers abstained from cigarettes on three separate occasions and received instead clonidine, placebo, or the benzodiazepine alprazolam. Clonidine and alprazolam diminished withdrawal symptoms. The two drugs suppressed anxiety, tension, irritability, and restlessness equally but clonidine had a greater effect than alprazolam on cigarette craving. These observations suggest that noradrenergic activity is a common feature in the pathophysiology of withdrawal and that a special relationship exists between central noradrenergic activity and craving.

Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review.

Overdose of tricyclic antidepressants (TCAs) leave no doubt that TCA drugs at high concentrations have serious cardiac effects. It has been assumed that, to a lesser extent, these effects would occur at usual therapeutic concentration. Recent prospective, plasma-level-controlled studies have improved our understanding of these drugs and proved these assumptions to be inaccurate. The most common serious cardiovascular complication of most tricyclic drugs is orthostatic hypotension. Tricyclic antidepressants are essentially free of any other serious adverse effects in depressed patients without cardiovascular disease. In patients with preexisting bundle-branch disease, there is a risk of heart block. On the other hand, patients with ventricular arrhythmias are likely to have their arrhythmias improve with TCA therapy. Finally, therapeutic doses of TCA have little adverse effect on left ventricular performance. As a result, TCA drugs can often be used to benefit depressed patients with overt heart disease.

Delusional depression. A distinct clinical entity?

The prognostic importance of delusions in the depressive syndrome had been a major focus of study before somatic therapies were available. Recently, the growing evidence that delusional depressives respond at a significantly lower rate to tricyclic antidepressants than do nondelusional depressives has revived this interest. That evidence is reviewed, and the demographic data and pretreatment clinical phenomenology of a series of hospitalized depressed patients were analyzed to see if differences existed between the delusional and nondelusional groups. Delusional unipolar depressives were less likely to recover while receiving placebo, had significantly more psychomotor retardation, and showed a trend toward fewer previous episodes than nondelusional unipolar depressives.

Treatment of bulimia with phenelzine. A double-blind, placebo-controlled study.

Twenty bulimic women of normal weight participated in a double-blind trial studying the effects of a monoamine oxidase inhibitor (MAOI). Nine women received phenelzine sulfate and 11 received placebo. Although phenelzine's side effects were a problem, the phenelzine-treated patients reported significantly fewer binges per week and had a lower Eating Attitudes Test score. Five of the nine phenelzine-treated patients ceased binging entirely and the other four reduced their binge frequency by at least 50%; none of the 11 placebo-treated patients stopped binging and only two reduced their binge frequency by 50% or more. These data demonstrate that phenelzine is significantly more effective than placebo in the treatment of bulimic women of normal weight and suggest a place for MAOIs in the treatment of bulimic patients capable of maintaining a tyramine-free diet.

Phenelzine vs placebo in 50 patients with bulimia.

To examine the efficacy of the monoamine oxidase inhibitor phenelzine sulfate in the treatment of bulimia, a double-blind, placebo-controlled trial was conducted. In 50 women who completed the trial, phenelzine was significantly superior to placebo in the reduction of binge frequency (64% vs 5%), in the fraction of patients who had ceased bingeing at the end of the trial (35% vs 4%), and in several measures of psychological state. The superiority of phenelzine over placebo was not confined to a depressed subgroup of patients. Although no patient experienced a hypertensive crisis during the study, other side effects of phenelzine were problematic and limit the usefulness of phenelzine in this population.

Tricyclic antidepressants in depressed patients with cardiac conduction disease.

The observation that fatalities from tricyclic antidepressant (TCA) overdose are associated with heart block and/or arrhythmias has led to concern about the cardiovascular effects of TCAs. Contrary to expectations, studies have shown TCAs to be relatively safe in patients without heart disease. However, it is unclear whether these drugs are also safe in patients with heart disease. This prospective study compared the risk of cardiovascular complication at therapeutic plasma concentrations of TCAs in 196 depressed patients, 155 with normal electrocardiograms and 41 with either prolonged PR interval and/or bundle-branch block. The prevalence of second-degree atrioventricular block was significantly greater in patients with preexisting bundle-branch block (9%) than in patients with normal electrocardiograms (0.7%). Orthostatic hypotension occurred significantly more frequently with imipramine than with nortriptyline, and in patients with heart disease.

Clinical implications of imipramine plasma levels for depressive illness.

Sixty depressed nonschizophrenic patients were admitted to a research unit. Following one drug-free week and one week of placebo, patients received 3.5 mg/kg of imipramine hydrochloride for 28 days. Plasma levels of imipramine and its metabolite desipramine hydrochloride (desmethylimipramine) were measured three times weekly and the relationship between plasma steady-state levels and clinical outcome was examined. Steady-state levels ranged from 50 to 1,050 ng/ml. There was a statistically and clinically significant relationship between plasma levels and response. The relationship existed across the entire sample, and was accentuated when the bipolar and unipolar nondelusional populations were examined. Because a strong relationship between sex and outcome was observed, the unipolar nondelusional patients were stratified by sex and a significant relationship still persisted. Only the unipolar delusional patients failed to demonstrate an association between blood level and clinical response.

Dexamethasone suppression test and plasma dexamethasone levels in bulimia.

A 1-mg dexamethasone suppression test (DST) was carried out in 66 women with bulimia and in 26 age- and sex-matched controls. Blood samples were obtained at 4 PM on the day following dexamethasone ingestion, and levels of cortisol and of dexamethasone in the plasma were measured. Thirty-two percent of the patients vs only 7% of the controls had plasma cortisol levels of 140 nmol/L (5 micrograms/dL) or greater following the DST (a positive DST). The plasma levels of dexamethasone varied substantially, and there was a significant inverse relationship between the plasma level of cortisol and that of dexamethasone. Patients with positive DST results had lower levels of plasma dexamethasone than did those with negative DST results, and the mean plasma level of dexamethasone was lower in the bulimic group than in the control group. These results suggest that factors other than a disturbance of hypothalamic-pituitary-adrenal activity may contribute to positive DST results in bulimia.

A correlational study of cardiovascular autonomic functioning and unipolar depression.

Cardiovascular autonomic functioning was assessed in 22 drug-free inpatients diagnosed by DSM-III criteria as having a unipolar depression. Sympathetic cholinergic, alpha- and beta-adrenergic activity were assessed via the measurement of forearm blood flow (FBF), digital blood flow (DBF), and the cardiac pre-ejection period (PEP), respectively. These parameters were correlated with total Hamilton score (HT) (using partial correlations to control for extraneous autonomic variables) to identify the specific autonomic correlates of unipolar depression. Significant negative correlations were found between HT and supine FBF and significant positive correlations between HT and PEP. Large effect-size, negative correlations (which approached significance) were found between HT and DBF. It is concluded that there is a specific autonomic profile of unipolar depression, characterized by a decrease in central sympathetic cholinergic outflow, coupled with increases in alpha-adrenergic and decreases in beta-adrenergic activity. Further, this profile is not merely a static hallmark of depression but covaries with the severity of the depression, independent of other autonomic activity.

EEG-monitored sleep in anorexia nervosa and bulimia.

We compared the EEG-monitored sleep of 8 women with anorexia nervosa and 16 normal weight women with bulimia to that of 14 normal women. The patients with anorexia nervosa spent less time asleep and spent less of their sleep time in Stage 1. The sleep of the normal weight patients with bulimia was remarkably similar to that of the controls. These data suggest that most patients with anorexia nervosa and bulimia do not exhibit the type of sleep disturbances characteristic of patients with major depressive illness.

Smoking cessation, clonidine, and vulnerability to nicotine among dependent smokers.

OBJECTIVE: This study examines the efficacy of clonidine in smoking cessation and the influence of gender, history of major depression, and measures of nicotine dependence. METHODS: The study was designed as a 10-week double-blind randomized comparison stratified for gender and major depression. Three hundred subjects who smoked cigarettes heavily were enrolled in the study. Abstinence from smoking was evaluated by self-report and verified by serum cotinine levels. RESULTS: Gender, major depression recurrent type, and measures of nicotine addiction were risk factors for treatment failure. There was no clonidine effect in men, but there was a modest effect in women (odds ratio, 2.01; 95% confidence interval, 1.00 to 4.10) that was most pronounced (odds ratio, 8.5; 95% confidence interval, 1.67 to 43.62) among women with the highest risks. CONCLUSION: Measures of addiction and major depression predict treatment failure. Together they are stronger predictors of outcome than drug. Clonidine is a limited aid in cessation, and drug effects come primarily from women at high risk for treatment failure. An increased risk for psychiatric complications after smoking cessation was apparent among smokers with histories of major depression, particularly bipolar disease.

Cigarette smoking: implications for psychiatric illness.

Psychiatry has been essentially uninterested in cigarette smoking and nicotine. However, it is the view of this author that both cigarette smoking and smoking cessation are highly relevant to the clinical psychiatrist in the care of patients and that they are potentially a source of important insights into psychopathology. To support that view, the author reviews the evidence that both major depression and depressive symptoms are associated with a high rate of cigarette smoking and that lifetime history of major depression has an adverse impact on smoking cessation. He also reviews the data available on the influence of cigarette smoking cessation on the course of major depression, the relationship between cigarette smoking and other psychiatric diagnoses, particularly schizophrenia, and the neuropharmacology that might underlie these associations. Finally, the implications of these relationships for psychiatry are discussed.

Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.

OBJECTIVE: The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. METHOD: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. RESULTS: All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.

Depression and the course of coronary artery disease.

Literature and folk wisdom have long linked depression and death; however, only recently have scientific studies examined the relation between them. Beginning in the 1970s, investigators compared mortality among patients treated for major depression and the general population. Nine of ten studies found an increased mortality from cardiovascular disease among depressed patients. However, such studies confound the relation between depression and its treatment. Community surveys circumvent this difficulty, but as these studies began to appear, other investigations revealed the strong association between depression and cigarette smoking, which made obvious a need to control for smoking. The first study to do this appeared in 1993, and not only did a relation between depression and mortality persist, but a relation between depression and the development of ischemic disease was revealed. In the past 2 years, six more community surveys have followed populations initially free of disease, and five have observed an increased risk of ischemic heart disease among depressed persons. Another research strategy is to start with subjects who have preexisting cardiovascular disease. Here, too, depression has consistently been associated with a worse outcome. In one well-designed study, patients with depression in the period immediately after a myocardial infarction were 3.5 times more likely to die than nondepressed patients. The basis of this association remains speculative. However, it is likely that the changes in the autonomic nervous system and platelets that are seen in depression account for a substantial portion of the association.

Depression, Delusions, and Drug Response.

Depressed patients with delusions were found to be markedly unresponsive to tricyclic drug therapy during an ongoing study of depressed patients. After four weeks of administration of imipramine hydrochloride, only 3 of 13 delusional depressed patients had responded to the drug, but 14 of 21 nondelusional depressed patients had responded. The authors conclude on the basis of these data and those of other researchers that delusional depressed patients should not be treated with tricyclic antidepressants and that current research with depressed patients should be reevaluated in the light of this finding.

Major depression following smoking cessation.

OBJECTIVE: The authors examined the incidence and predictors of major depression following successful smoking cessation treatment, with special attention to the influence of past major depression. METHOD: Three-month follow-up data were obtained from 126 subjects who successfully completed a 10-week smoking cessation program. RESULTS: The 3-month incidence of new major depression following treatment for nicotine dependence was 2%, 17%, and 30% among subjects with histories of no major depression, single major depression, and recurrent major depression, respectively. A history of major depression and persistent withdrawal symptoms independently predicted posttreatment major depression. CONCLUSIONS: Continued patient care beyond the 2-4-week period associated with the nicotine withdrawal syndrome is indicated when abstinence is attempted by smokers with prior major depression.

Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia.

OBJECTIVE: The popularity of selective serotonin reuptake inhibitors stems from their apparent efficacy for numerous disorders and their favorable side effect profile. However, several studies have suggested that selective serotonin reuptake inhibitors may be relatively ineffective for treating melancholia. The objective of this study was to compare the responses to fluoxetine and nortriptyline of older patients with both severe depression and heart disease. METHOD: The outcome of 22 hospitalized patients with unipolar depression and heart disease who were treated with fluoxetine was compared to the outcome of 42 comparable patients treated with nortriptyline. The average age of the fluoxetine group was 73 years, and their mean pretreatment score on the Hamilton Depression Rating Scale was 26; the average age of the nortriptyline group was 70, and their mean pretreatment Hamilton score was 28. RESULTS: Of the 42 nortriptyline-treated patients, 28 were responders, six were nonresponders, and eight dropped out. The intent-to-treat response rate was 67% (28 of 42), and the response rate of the melancholic patients who completed the nortriptyline trial was 83% (20 of 24). Of the 22 fluoxetine-treated patients, five were responders, 13 were nonresponders, and four dropped out. The intent-to-treat response rate was 23% (five of 22), and the response rate of the melancholic patients who completed the fluoxetine trial was 10% (one of 10). CONCLUSIONS: Fluoxetine appears to be significantly less effective than nortriptyline for treating hospitalized elderly patients with unipolar major affective disorder, especially those with the melancholic subtype and concurrent cardiovascular disease.

Tricyclic nonresponders: phenomenology and treatment.

In an attempt to identify characteristics of tricyclic antidepressant nonresponders, the authors reviewed the records of inpatients with unipolar, nondelusional depression who had received adequate treatment (confirmed by plasma level determination) with tricyclics. The 17 patients who failed to respond were compared to a group of tricyclic responders with respect to demographic and phenomenologic variables. Although the nonresponders tended to have more previous episodes of depression and higher anxiety scores on the pretreatment Hamilton scale than the responders, they could not be distinguished from the responders by clinical or demographic data. All of the patients who failed to respond to tricyclics subsequently responded to monoamine oxidase inhibitors and/or ECT.

Effect of history of alcoholism or major depression on smoking cessation.

The authors examined the influence of a history of alcoholism or major depression on smoking cessation for 220 subjects. The success rate of recovering alcoholics was comparable to that of nonalcoholics, comorbidity of alcoholism and major depression exerted a detrimental effect, and smoking cessation did not precipitate an alcoholic relapse.

The dexamethasone suppression test in bulimia.

Nineteen (35%) of 55 women with bulimia failed to exhibit cortisol suppression after dexamethasone administration. Although there was no statistically significant difference between suppressors and nonsuppressors on any clinical variable, there was a higher frequency of major depression among nonsuppressors.