Narcolepsy. Pharmacotherapy of impaired affect in recovering schizophrenic patients. Fluvoxamine and clomipramine in the treatment of cataplexy. The treatment of accessory symptoms in narcolepsy: a double-blind cross-over study of a selective serotonin re-uptake inhibitor (femoxetine) versus placebo. Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.
Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence. Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.
                In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.
                For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.
                Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature. Fluvoxamine 25-200 mg daily and clomipramine 25-200 mg daily were given for separate three week periods to 18 subjects with narcolepsy and cataplexy. Both drugs improved cataplexy but not narcolepsy. Fluvoxamine was less active than clomipramine, but both drugs abolished cataplexy in individual subjects. Gastrointestinal side effects prevented treatment with fluvoxamine in five subjects. All patients completed the clomipramine phase of the trial, but two men complained of delayed ejaculation. Fluvoxamine is a more potent inhibitor of 5-hydroxytryptamine (5-HT) reuptake in some systems, but not in others. It is therefore uncertain whether the greater anticataplectic effect of clomipramine is due to a greater inhibition of 5-HT reuptake or to other mechanisms. A randomized, double-blind cross-over trial was carried out in 10 patients with narcolepsy to evaluate the effect of 600 mg femoxetine versus placebo. In comparison to placebo, femoxetine treatment resulted in a significant decrease in both the number and severity score of cataplectic attacks per day. There were also significantly fewer attacks of sleep paralysis, whilst the effects on nightmare and hypnogenic hallucinations were minor. The frequency of sleep attacks decreased slightly during femoxetine treatment, but the overall estimated sleep time during the day and excessive daytime sleepiness remained un-affected. An ambulatory sleep recording for 48 h one week after the start of the femoxetine and placebo period showed that femoxetine treatment resulted in a significant decrease in the total time spent in REM sleep. The side-effects of femoxetine were restricted to transient nausea in 2 patients. It is concluded that femoxetine or other selective serotonin reuptake inhibitors may be a useful alternative for narcoleptic patients who experience troublesome side-effects with tricyclic antidepressants. The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence.
                A multi-arm, modified blinded, placebo-controlled design was used.
                The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU).
                Participants met criteria for cocaine dependence during a 2-week screening period.
                Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study.
                Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period.
                None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated.
                This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.
Since the last version of this review no new studies were found.
There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.