Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features.

The aim of this multicenter, randomized, double-blind, 8-week study was to compare the antidepressant efficacy and tolerability of mirtazapine and venlafaxine in the treatment of hospitalized patients with DSM-IV diagnosis of severe depressive episode with melancholic features. Patients with a baseline score of > or = 25 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) were randomly assigned to receive treatment with either mirtazapine (N = 78, 15-60 mg/day) or venlafaxine (N = 79, 75-375 mg/day, twice a day) in a rapid up-titration schedule. Efficacy was assessed with the Montgomery-Asberg Depression Rating Scale (MADRS), HAM-D-17, and Clinical Global Impression scale, and quality of life was assessed with the Quality of Life, Enjoyment, and Satisfaction Questionnaire and Quality of Life in Depression Scale. Tolerability was assessed with the Utvalg for Kliniske Undersogelser (UKU) side effect scale and by reporting adverse events. Both drugs were effective in reducing overall symptoms of depression, showing substantial reductions in group mean MADRS scores (-20.1 for mirtazapine and -17.5 for venlafaxine) and HAM-D-17 scores (-17.1 for mirtazapine and -14.6 for venlafaxine) at the end of the treatment. Although not statistically significant, at all assessment times higher percentages of patients treated with mirtazapine were classified as responders (> or =50% reduction) on the HAM-D (at endpoint, 62% vs. 52%) and MADRS (at endpoint: 64% vs. 58%). Likewise were the percentages of remitters (HAM-D score < or =7; MADRS score < or =12) also higher in the mirtazapine group. A statistically significant difference favoring mirtazapine was found on the HAM-D Sleep Disturbance factor at all assessment points (p < or = 0.03). Both treatments were well tolerated. Although slightly more subjects treated with mirtazapine reported at least one adverse event, a statistically significantly higher percentage of patients treated with venlafaxine (15.3%) than mirtazapine (5.1%) dropped out because of adverse events (p = 0.037). Quality of life improved in both treatment groups. In this study, treatment with mirtazapine resulted in a trend toward more responders and remitters than treatment with venlafaxine and in significantly fewer dropouts as a result of adverse events.

The St. Hans Rating Scale for extrapyramidal syndromes: reliability and validity.

The St. Hans Rating Scale (SHRS) is a multidimensional rating scale for the evaluation of neuroleptic-induced hyperkinesia, parkinsonism, akathisia and dystonia. This scale and the Abnormal Involuntary Movement Scale (AIMS) were tested by 7 raters (2 experienced, 2 less experienced and 3 totally inexperienced) in 30 psychiatric patients with tardive dyskinesia (TD). The test was performed 3 times in the same patients: 1) live evaluation during a video recording, 2) evaluation 2 weeks later from the videotape, and 3) evaluation after another 2 weeks from the same videotape. The intrarater reliability was high in the experienced group (0.91-0.96 for SHRS hyperkinesia scale, 0.80-0.84 for AIMS, and 0.82-0.97 for SHRS total parkinsonism). No significant changes occurred from live to video evaluation. The interrater reliability coefficient for the experienced group was also high: 0.89-0.95 for the SHRS hyperkinesia scale, 0.76-0.85 for the AIMS scale and 0.95-0.98 for the SHRS parkinsonism scale. The less experienced and the inexperienced raters had coefficients for intra- and interrater reliability that were 0.10 and 0.20 lower, respectively. The SHRS parkinsonism scale had a high construct validity, as determined by the homogeneity coefficients of Cronbach (0.82) and Loevinger (0.43). The corresponding coefficients for the hyperkinesia scales were low, in agreement with the individual distribution of TD (only about 50% present extremity dyskinesia and less than 25% facial, head and trunk dyskinesia, independent of the severity of the syndrome). Finally, convergent validity was found between the SHRS hyperkinesia scale and AIMS and divergent validity between all of the other scales.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of citalopram, a specific serotonin uptake inhibitor, in tardive dyskinesia and parkinsonism.

Serotonin (5-HT) has been proposed to exert an inhibitory effect on central dopamine activity, so increased brain 5-HT would be expected to reduce tardive dyskinesia (TD). Therefore a new antidepressant, a selective 5-HT uptake inhibitor, citalopram, was evaluated in 13 psychiatric patients with TD, 11 of whom also had neuroleptic-induced parkinsonism. Drug effects during active treatment (20-40 mg/day for 3 weeks) and pre- and posttreatment placebo periods were scored blindly from videotapes recorded weekly. TD, parkinsonism, and eyeblinking rates were unchanged. Psychiatric symptoms showed no significant changes, and no side effects were reported. The data suggest that increasing 5-HT activity by 5-HT uptake inhibitors has no significant beneficial effect in TD, but citalopram may be advantageous in the treatment of depressed patients who also have TD, as this drug does not aggravate TD as do tricyclic antidepressants.

Effects of serotonergic and anticholinergic drugs in haloperidol-induced dystonia in Cebus monkeys.

In rodents, serotonin (5-HT) antagonists counteract behavioral and biochemical effects of neuroleptic drugs. Therefore, we have studied the effect of different 5-HT drugs and one anticholinergic drug in acute dystonia in five cebus monkeys chronically treated with haloperidol. Acute dystonia induced by subcutaneous injections of haloperidol was slightly reduced by the 5-HT antagonist methysergide (4.0 mg/kg), while mianserin, ketanserin, and ritanserin (R 55 667; a new selective and potent 5-HT receptor blocker) had no effect. This was contrasted by the marked antidystonic effect of the anticholinergic drug biperiden (0.05-1.0 mg/kg). The 5-HT agonist citalopram, a specific 5-HT uptake inhibitor, had no significant effect. It is concluded that 5-HT antagonists have no useful effect in neuroleptic-induced dystonia.

Effects of mianserin in neuroleptic-induced parkinsonism.

It has been proposed that serotonin (5-HT) antagonists counteract neuroleptic-induced extrapyramidal symptoms by disinhibition of dopamine activity. The effects of the 5-HT antagonist mianserin, the anticholinergic drug procyclidine and placebo were evaluated in 16 psychiatric patients with chronic neuroleptic-induced parkinsonism in a double-blind cross-over trial. The patients received each drug in random order in 3-week periods separated by washout periods of 2 weeks. The effect of mianserin did not significantly differ from that of placebo, while parkinsonian symptoms were significantly reduced during treatment with procyclidine (P less than 0.05). Although mianserin was ineffective in chronic neuroleptic-induced parkinsonism, it cannot be excluded that 5-HT antagonists may be effective in the treatment of acute extrapyramidal side effects.

Behavioral aspects of serotonin-dopamine interaction in the monkey.

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.

Effects of apomorphine and haloperidol on "spontaneous" stereotyped licking behaviour in the Cebus monkey.

Three recently arrived drug naive Cebus apella monkeys with "spontaneous" stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05-0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25-1.0 mg/kg) and haloperidol (0.01-0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.

Fluperlapine in tardive dyskinesia and parkinsonism.

Fluperlapine, a new clozapine-like neuroleptic drug with weak affinity for dopamine receptors, was evaluated in a blind, placebo controlled trial in 11 patients with stable hyperkinesia (ten with tardive dyskinesia (TD) and one with spontaneous dyskinesia). Drug effects during active treatment (200-600 mg/day) and during pre- and post-treatment placebo periods were determined by scoring randomly sequenced videotapes of TD and parkinsonian symptoms recorded weekly during standardized examinations. TD score was unchanged, while parkinsonism slightly decreased (P less than 0.05) and eye-blinking rates increased (P less than 0.05). Psychiatric symptoms showed no significant changes, although positive psychotic symptoms diminished in four patients. Side effects included dizziness, sedation and constipation. The effects in movement disorders found in this study may imply that fluperlapine is less liable than traditional neuroleptics to induce acute extrapyramidal side effects and tardive dyskinesia and is particularly beneficial in the treatment of patients vulnerable to neurological side-effects.

Effect of gamma-vinyl GABA in tardive dyskinesia.

gamma-Vinyl GABA (gamma-aminobutyric acid), a drug that increases brain GABA via GABA transaminase inhibition, was evaluated in a blind, placebo-controlled trial in 10 patients with stable tardive dyskinesia. Drug effects during active treatment (2 to 6 g/day) and during pre- and posttreatment placebo periods were determined by scoring randomly sequenced videotapes of tardive dyskinesia and parkinsonian symptoms recorded weekly during standardized examinations. Tardive dyskinesia was significantly reduced, and correlated to increased parkinsonism. Eye blinking rates decreased, but psychiatric symptoms were unchanged during treatment.

Chronic psychosis in epilepsy. A clinical investigation of 29 patients.

A clinical study comprising psychiatric, psychological and neurological examination of 29 patients suffering from long-term psychosis and severe epilepsy was performed. Only five patients fulfilled the diagnostic criteria of schizophrenia. They differed from the rest of the patients by being less organic and having infrequent laterality to the left of their epileptogenic focus. They were regarded as genuine schizophrenics, while the pathogenesis of the remaining sample was considered multifactorial, including both organic and psycho-social causes.

The effect of tetrahydroisoxazolopyridinol (THIP) in tardive dyskinesia: a new gamma-aminobutyric acid agonist.

gamma-Aminobutyric acid (GABA) agonists have been proposed for the treatment of tardive dyskinesia, but their therapeutic potential has been limited by side effects and toxicity. To elucidate further the role of GABA in neuroleptic-induced dyskinesias, we evaluated tetrahydroisoxazolopyridinol (THIP), a new, less toxic GABA analog and GABA receptor agonist, in both a dose-finding (single-dose) pilot study with five patients and a longer (four-week) placebo-controlled study with 13 patients. The patients were videotaped during a standardized examination; tardive dyskinesia, parkinsonian symptoms, and eye-blinking rates were rated blindly and randomly. The maximal short-term dose of THIP was 10 to 25 mg, whereas in the longer-term study the highest daily dose ranged from 20 to 120 mg. Tardive dyskinesia was unchanged during THIP treatment, but preexisting parkinsonism increased significantly and eye-blinking rates decreased. Psychiatric symptoms showed no significant changes, although tension and depression lessened. Side effects included sedation, confusion, dizziness, vomiting, and myoclonic jerks. Although THIP is not an effective new treatment for tardive dyskinesia, more specific GABA agonists should be evaluated in future studies of this syndrome.

Epilepsy and psychosis.

In an attempt to survey the evidence of causal relationship between epilepsy and chronic psychosis the literature has been searched with respect to frequency of psychoses, psychopathological classifications and correlations between biological and behavioural variables. It is concluded that a unitary theory of aetiology in epileptic psychosis can not be maintained. The psychotic pictures seldom fulfill the Bleulerian concept of schizophrenia, and consequently the term schizophrenia-like should be avoided. With respect to future investigations a prospective research method is advocated.

High-dose destyrosine-gamma-endorphin in tardive dyskinesia.

Destyrosine-gamma-endorphin (DTGE) has purported neuroleptic properties, although the findings have been conflicting. Four chronic psychotic inpatients with neuroleptic-induced dyskinesias were treated with single injections of placebo and DTGE in high doses (20-120 mg). No consistent differences were found in tardive dyskinesia, parkinsonism, eye-blinking rates, or mental status. Laboratory tests were unchanged. It is concluded that acute DTGE treatment has no beneficial effect in drug-induced dyskinesia.

Effect of des-tyrosine-gamma-endorphin in tardive dyskinesia.

The endorphin neuropeptides may have neuroleptic-like effects on dopamine function and may be antischizophrenic. Ten chronic psychotic patients with neuroleptic-induced tardive dyskinesia and parkinsonism received placebo and des-tyrosine-gamma-endorphin (DT gamma E). Drug effects on movement disorders and eye-blinking rates were assessed by blind evaluations of randomly sequenced videotapes made during standardized examinations before and 30, 60, and 120 minutes after each injection and at 24 hours postinjection on days of consecutive treatment. Changes in schizophrenic symptoms were evaluated openly with the schizophrenia subscale of the Comprehensive Psychiatric Rating Scale. There were no significant effects of DT gamma E on any parameter and no side effects. This suggests that DT gamma E, within the tested dose range, does not influence the pathophysiology of neuroleptic-induced dyskinesias or chronic schizophrenia or have neuroleptic properties. However, DT gamma E is well tolerated and should be tested with higher doses during prolonged treatment.

Vasopressin in anergic schizophrenia. A cross-over study with lysine-8-vasopressin and placebo.

Sixteen out of 19 patients suffering from chronic anergic schizophrenia completed a placebo-controlled cross-over study with lysine-8-vasopressin (LVP), following a schedule of 1 week of placebo, 3 weeks of LVP, starting with 22.5 IU/day, gradually increased to 67.5 IU/day, and finally 4 weeks of placebo. The psychic state was evaluated with the Brief Psychiatric Rate Scale (BPRS), during weekly live interviews, and following videotaped BPRS interviews at the beginning and end of the LVP period, and at the end of the final placebo period. Symptoms of parkinsonism and tardive dyskinesia were also videotaped during a standardized examination at the same intervals. The videotapes were subsequently randomized and evaluated blindly. The results of liver interviews showed a significant (P less than 0.05) decrease in the BPRS anergic factor after 2 and 3 weeks of LVP treatment, but there were no changes in any single item, other BPRS factors, or the BPRS total score. The results of the videotape evaluations showed that the BPRS thinking disorder factor was significantly (P less than 0.05) decreased after 3 weeks of LVP, whereas the BPRS score was unchanged. No consistent changes in parkinsonism or tardive dyskinesia were found. Although side effects were few, six patients became agitated or aggressive during the LVP treatment. The beneficial effect on thought disorder and anergia, but the absence of global effects on the schizophrenic syndrome, illustrates the need for further research with other vasopressin analogues. The advantages and disadvantages of live and videotaped psychiatric interviews are also discussed.