COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers.

The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0 mg per 70 kg doses of nicotine, administered 30 min apart. Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.

Increased anxiogenic effects of caffeine in panic disorders.

The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.

Drug-responsive symptoms in melancholia.

Depressive symptoms present in 43 patients with unipolar nondelusional melancholia were studied to determine which symptoms were the best measures of response to desipramine hydrochloride. An extended Hamilton Depression Scale was used to identify symptoms that were present frequently. We then determined which symptoms improved in direct relation to achievement of therapeutic plasma desipramine concentrations, using multiple regression analysis to account for pretreatment symptom severity. In ten symptoms, improvement was significantly associated with desipramine treatment. These ten symptoms seem to be the best measure of drug response during tricyclic antidepressant treatment in patients with nondelusional melancholia.

Subjective complaints during desipramine treatment. Relative importance of plasma drug concentrations and the severity of depression.

Subjective complaints, including those traditionally considered tricyclic antidepressant side effects, were studied in 43 depressed inpatients during a three-week trial of desipramine hydrochloride. Multiple regression analysis was employed to examine the independent relationship of pretreatment symptoms, concurrent depression, and plasma drug concentrations to subjective complaints reported during treatment. As a group, subjective complaints were positively associated with pretreatment symptoms and the concurrent severity of depression, but not with plasma desipramine concentration. Of the 23 individual complaints studied, three increased during treatment and nine improved. Only two complaints, tremors and light-headedness, were significantly associated with plasma drug concentration. The data indicate that during initial treatment of severe depression with desipramine, subjective complaints are more likely to be symptoms of depression than side effects of the drug and that plasma desipramine determinations would not be useful for predicting or avoiding these complaints. The best management of most symptoms studied was adequate treatment of the depression.

A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression.

Prompted by a recent study suggesting that the combination of desipramine hydrochloride and fluoxetine down-regulates beta-adrenergic receptors more rapidly than either drug alone, we administered both desipramine and fluoxetine to 14 inpatients with major depression in an open, 4-week trial. Desipramine plasma levels drawn 24 hours after an initial standardized dose were used to rapidly adjust desipramine dosage and compensate for the interactive effects of fluoxetine on desipramine levels in the blood. Responses were retrospectively compared with those of 52 inpatients who were descriptively similar and previously treated in the same setting with desipramine alone. Response was significantly more rapid in the group that received both drugs. One week after treatment began, the mean change in Hamilton Depression Rating Scale scores was 42% in the group that received both drugs and 20% in the group that received desipramine alone (Mann-Whitney U test, P = .007). Two weeks after administration of the drugs, the mean change in scores of the group that received both drugs was 60%, while a 30% change was noted in the patients treated with desipramine alone (P = .001). Ten (71%) of the 14 patients in the group that received both drugs completely remitted (change in Hamilton Depression Rating Scale score of greater than 75%, and final score of less than 7) within 4 weeks, while few patients treated with desipramine alone met these criteria within 4 weeks. This preliminary study suggests that treatment with both desipramine and fluoxetine is a rapid and effective strategy for treatment of major depression, and supports recent hypotheses of noradrenergic-serotonergic synergism.

Major adverse reactions during desipramine treatment: relationship to plasma drug concentrations, concomitant antipsychotic treatment, and patient characteristics.

Major adverse reactions interrupting drug therapy during treatment of 84 patients with desipramine hydrochloride were studied to determine their relationship to desipramine plasma concentrations and other clinical variables. The frequency of adverse reactions was higher in patients over 60 years old (39%), and in patients also receiving antipsychotic medications (32%), but low in patients under 60 years old (7%). Desipramine plasma concentrations in patients having side effects did not differ significantly from those in patients without side effects. Steady state desipramine plasma concentrations did not increase with age. Symptomatic orthostatic hypotension, the most common side effect encountered, occurred early in treatment at low desipramine plasma concentrations. Other side effects, usually described as anticholinergic, occurred exclusively in the 34 patients receiving both desipramine and antipsychotic drugs. The concentration of 2-hydroxy-desipramine, the total concentration of 2-hydroxy-desipramine and desipramine, and the ratio of 2-hydroxy-desipramine to desipramine were not higher in 11 patients having side effects than in a comparison group without side effects.

Desipramine facilitation of initial cocaine abstinence.

We conducted a double-blind, random assignment, six-week comparison of desipramine hydrochloride (n = 24), lithium carbonate (n = 24), and placebo (n = 24) treatments for cocaine dependence. Subjects were 72 outpatient cocaine abusers who met DSM-III-R dependence criteria for cocaine but not for other substance abuse. Subjects in each treatment group were similar in history of cocaine and other substance abuse, cocaine craving, sociodemographics, and other psychiatric comorbidity. Desipramine, compared with both other treatments, substantially decreased cocaine use. Lithium treatment outcome did not differ from that of placebo. Desipramine-treated subjects attained contiguous periods of abstinence substantially more frequently than subjects receiving lithium or placebo. Fifty-nine percent of the desipramine-treated subjects were abstinent for at least three to four consecutive weeks during the six-week study period, compared with 17% for placebo and 25% for lithium. Cocaine craving reductions were also substantially greater in the desipramine-treated subjects. Establishment of initial abstinence is the first stage in recovery from cocaine dependence. Our findings indicate that desipramine is an effective general treatment, for this first treatment stage, in actively cocaine-dependent outpatients.

Plasma free homovanillic acid (HVA) as a predictor of clinical response in acute psychosis.

The relationship of plasma free homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) to early clinical response was prospectively studied in a new series of acutely psychotic inpatients given a fixed dose of perphenazine elixir for 10 days. Elevated pretreatment plasma HVA but not MHPG was significantly associated with good response. Change in HVA was correlated with a favorable response and a significant decline in MHPG was found in responders. Results suggest that HVA can provide a useful clinical predictor of response, and that both dopamine metabolism and noradrenergic functioning, as measured by plasma HVA and MHPG, are reduced in effective neuroleptic treatment.

Lithium in combination with perphenazine: effect on plasma monoamine metabolites.

The addition of lithium to perphenazine altered the pattern of plasma homovanillic acid (HVA) during the course of treatment for acute psychosis. In the perphenazine-treated group plasma HVA declined significantly by days 7-9 of treatment, whereas in the perphenazine-plus-lithium group plasma HVA tended to increase. The pattern for plasma methoxyhydroxyphenethyl-glycol (MHPG) was not significantly different for the two groups. The addition of lithium to a neuroleptic may enhance the metabolism of dopamine.

Plasma catecholamine metabolites and treatment response at neuroleptic steady state.

Using either haloperidol or perphenazine in a fixed-dose protocol, plasma free homovanillic acid (HVA) and methoxyhydroxyphenethylglycol (MHPG) were decreased in 37 nonorganic psychotic inpatients at neuroleptic steady state (7-9 days) in comparison with pretreatment values. The data indicate that the magnitude of the decline in HVA and MHPG was associated with treatment response and not with neuroleptic plasma levels.

Effect of alpha-methyl-para-tyrosine on response to cocaine challenge.

This study evaluated the effect of an acute reduction in catecholamine synthesis produced by alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, on cocaine-induced euphoria. In a blinded, placebo-controlled study, AMPT (1 g p.o. T.I.D.) was given to 10 non-treatment-seeking cocaine abusers prior to intranasal administration of 2 mg/kg cocaine. AMPT, but not placebo, reduced plasma levels of the dopamine metabolite homovanillic acid and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol. AMPT also elevated prolactin levels, indicating inhibition of the tuberoinfundibular dopamine system. AMPT pretreatment produced a trend toward diminished cocaine "high" AMPT also tended to lower heart rate and blood pressure responses to cocaine, but had no effect on serum cocaine levels. Although we cannot rule out the therapeutic potential of the depletion strategy, our results with AMPT alone, at this dose, do not strongly support it.

Nonlinear desipramine kinetics: prevalence and importance.

Tricyclic antidepressant plasma levels have been used to guide dose adjustment in nonresponding patients, and recently 24-hour drug levels have been advocated for predicting therapeutic doses. Both methods of dose adjustment assume linear drug kinetics. Recent reports have suggested that desipramine kinetics are nonlinear, but the samples described were small, six subjects or fewer. In the current study, plasma desipramine concentrations were examined in 42 inpatients who were depressed who had achieved steady-state conditions with a low initial dose and subsequently with a higher dose. Desipramine concentrations increased significantly more than that predicted by the dose increase; however, only one third of the sample had substantial nonlinear changes (an increase in the concentration 50% greater than expected). In the remainder of the sample, disproportionate increases in plasma concentrations were not likely to be of clinical consequence.

Antidepressant activity of 2-hydroxydesipramine.

We describe the relationship of 2-hydroxydesipramine (OH-DMI) plasma levels and response in a prospective DMI study in which dosage was rapidly adjusted to achieve a relatively uniform DMI plasma level. In prior studies, OH-DMI plasma levels were not related to response, but in these fixed-dose protocols the effects of OH-DMI are easily obscured by the higher concentrations of the parent drug. We hypothesized that in this study a contribution of OH-DMI to response might become apparent because DMI levels were relatively constant. Inpatients with nonpsychotic, unipolar DSM-III major depression who remained depressed (Hamilton score greater than 18) after 1 week of hospitalization without medication received a 4-week DMI trial. Twenty-four-hour drug plasma levels were used to adjust dose to reach a target DMI steady-state plasma level. Twenty-seven patients completed the trial. On every measure of response, total drug levels (DMI + OH-DMI) were more strongly correlated with outcome than were DMI levels alone. With multiple regression, both DMI and OH-DMI levels were independently and significantly associated with response. These findings suggest that OH-DMI has antidepressant activity.

Clinical implications of 2-hydroxydesipramine plasma concentrations.

The clinical utility of 2-hydroxydesipramine (2-OH-DMI) measurements was evaluated by examining the relationship of 2-OH-DMI concentrations in plasma to clinical outcome and side effects in depressed inpatients treated with desipramine (DMI). Studies were performed in responders and nonresponders to treatment and in patients experiencing subjective side effects or major adverse reactions necessitating interruption of treatment. Unlike DMI concentrations, 2-OH-DMI concentrations did not correlate with response. Summing the concentrations of parent drug and metabolite (DMI + 2-OH-DMI) did not improve the correlation over that achieved with DMI alone. Neither DMI, 2-OH-DMI, nor their sum correlated with subjective side effect totals or major adverse reactions. While our data do not permit any conclusions regarding the clinical activity of 2-OH-DMI, they suggest that its routine measurement in plasma is not likely to be useful in the management of depression.

Desipramine hydroxylation: variability and effect of antipsychotic drugs.

Steady-state plasma concentrations of desipramine (DMI), unconjugated 2-OH DMI, and total 2-OH DMI were measured in 82 depressed inpatients, 35 of whom were concurrently receiving a phenothiazine or butyrophenone antipsychotic drug. In the patients not on an antipsychotic, the ratio of unconjugated metabolite to parent varied from 0.01 to 1.5, with a median of 0.48, and was inversely related to the parent drug level. Antipsychotic drug was associated with higher DMI levels and a lower proportion of OH-metabolite (median, 0.23). In both groups the unconjugated form accounted for only about 10% of the total metabolite. No relationship of age, sex, drinking history, or smoking to DMI or 2-OH DMI levels was found.

Neuroloeptic effect on desipramine steady-state plasma concentratins.

The authors examined the effect of neuroleptic drugs on desipramine steady-state plasma concentration in 30 patients who received similar milligram per kilogram doses of desipramine. Fifteen of these patients also received a neuroloeptic drug and had desipramine plasma levels twice that of the 15 patients who received dispiramine alone. The authros discuss the implications of the magnitude of this difference for therapeutic response and incidence of side effects.

Neuroleptic dose and desipramine concentrations during combined treatment of unipolar delusional depression.

The relationship of response to neuroleptic dose and desipramine plasma concentration was examined in 31 patients with unipolar delusional depression. The patients received either perphenazine or haloperidol for 1-2 weeks, after which desipramine, 2.5 mg/kg of body weight per day, was added. Neuroleptic dose varied among patients but was constant within individuals. Global response was rated retrospectively on the basis of outcome during the fourth week of combined drug treatment. Responders had higher plasma desipramine concentrations and had received higher neuroleptic doses than nonresponders had. The effective threshold level for desipramine was similar to that previously described for nonpsychotic melancholic patients, suggesting a similar mode of action for the drug in the two disorders.

Effects of desipramine on clinical liver function tests.

Results of liver function tests in 46 depressed patients changed little during treatment with desipramine and were uncorrelated with drug plasma levels. The findings suggest that tricyclic-associated hepatitis, rather than being dose dependent, is an uncommon, idiosyncratic phenomenon.

Value of the DST for predicting response of patients with major depression to hospitalization and desipramine.

The authors examined the value of the dexamethasone suppression test (DST) for predicting response of patients with unipolar, nonpsychotic major depression to 1 week of hospitalization without antidepressant drugs and to a 4-week trial of desipramine at a fixed plasma level. The rates of response to hospitalization without drug treatment (defined as a score of 12 or less on the Hamilton Rating Scale for Depression) were not significantly different for the patients with a positive DST and those with a negative DST. This finding differs from those of prior studies of the DST and response to placebo. The responses of the DST-positive and DST-negative patients to desipramine also did not differ, a finding that replicates those in some prior reports.

Tricyclic antidepressants: plasma levels and clinical findings in overdose.

Following amitriptyline or imipramine overdose by 30 patients, total plasma concentrations ranged from 29 to 1732 ng/ml but did not correlate well with physical findings or most electrocardiographic changes. Only those patients with a QRS interval greater than 0.1 second had significantly elevated plasma levels. However, a plasma level ratio of the parent drug (amitriptyline, imipramine) to its respective N-desmethyl metabolite (nortriptyline, desmethylimipramine) greater than or equal to 2.0 was associated with an acute overdose. This ratio was more useful than total plasma levels in differentiating an overdose from a therapeutic dose with associated toxicity and an elevated steady-state plasma level.