Jes Gerlach

Tolerability and therapeutic effect of clozapine: a retrospective investigation of 216 patients treated with clozapine for up to 12 years

ABSTRACT– Two hundred and sixteen psychiatric patients (183 men and 33 women) hospitalized in Set. Hans Hospital were treated with clozapine between 1971–1983. All had been treated previously with one or more neuroleptic(s) and had either failed to respond adequately, or their response was limited by side effects. Eighty‐five patients were treated exclusively with clozapine, while the remaining 131 received additional medication, mainly other neuroleptic drugs. The mean clozapine dosage was 317 mg/day (range 50‐1200), and the mean duration of treatment was 2 3/4 years (range 1/12‐12). The tolerability to clozapine was determined by an evaluation of haematological changes, pronounced side effects and mortality. One patient treated with clozapine (8 months) and nitrofurantoin (8 days) developed a reversible granuiocytopenia. One patient (treated with a combination of drugs) had clinically insignificant depression of the leucocytes and three of segmented granulocytes. Seven had a reduction in thrombocytes. Two patients developed cardiac insufficiency, and four epileptic seizures. None of the patients treated exclusively with clozapine developed neurological side effects. A global estimation of therapeutic effect revealed that clozapine alone or in combination with other neuroloptic drugs was significantly better than previous antipsychotic therapy, although 47‐63 % of the patients showed no change. It is concluded that clozapine is a potent antipsychotic drug offering particular advantages in the treatment of schizophrenic patients with a pronounced symptomatology and tendency towards developing extrapyramidal side effects. Caution is advised in patients with cardiac insufficiency and epilepsy. There appears to be a slight risk of granuiocytopenia, and therefore the present monitoring of WBC should continue in order to prevent this reaction and to obtain more complete information regarding risk of granuiocytopenia.

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.

Bromocriptine and imipramine in endogenous depression: A double-blind controlled trial in out-patients

Among 33 out-patients with endogenous depression, 16 were treated with bromocriptine (10-60 mg/day, mean 34) and 17 with imipramine (75-250 mg/day, mean 143). The total score on the Hamilton Rating Scale decreased during 6-week treatment from 19.9 to 7.8 in the bromocriptine group (P less than 0.001) and from 20.1 to 6.1 in the imipramine group (P less than 0.001). There was no significant difference between the two groups. The main side-effects were for bromocriptine: nausea, dizziness, and headache; for imipramine; dryness of mouth, dizziness, and sweating. This study suggests an antidepressant effect of bromocriptine although, due to the possibility of Type II error, it may not necessarily be equal to that of imipramine.

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response, side effects, serum haloperidol, and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.

Dopamine, acetylcholine, and GABA effects in acute dystonia in primates

Neurological side effects associated with neuroleptic drugs result from a complex interaction of multiple neurotransmitters. To clarify the etiology of neuroleptic-induced acute dystonic reactions, monkeys (Cercopithecus aethiops) were treated with haloperidol at doses sufficient to evoke dystonia, and the effects of agents that influenced dopaminergic, cholinergic, or GABAergic neurotransmitters were evaluated. Apomorphine, a dopamine (DA) agonist, and biperiden, an acetylcholine (ACh) antagonist, decreased acute dystonia, whereas α-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis, and physostigmine, and ACh agonist, increased the symptoms. Muscimol, a GABA agonist, increased the dystonias in a dose-dependent way, and GABA inhibition with picrotoxin also aggravated dystonia, complicated by systemic intoxication and seizures. The reciprocal interaction between DA and ACh influences is consistent with clinical findings and animal models of dyskinesias. Dystonia may also be modulated by GABAergic substrates, but the results suggest complex interactions among DA, ACh, and GABA neurotransmission. Symptoms involving the orofacial, limb, and trunk regions, and purposeless overactivity are discussed in comparison with acute and tardive neuroleptic-induced movement disorders.

The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys

Xanomeline is a muscarinic M1/M4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimers disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (−)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5–3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits D-amphetamine- and (−)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.

Clozapine versus typical antipsychotics a retro- and prospective study of extrapyramidal side effects

Schizophrenic patients in long-term neuroleptic monotherapy with clozapine (n=100) and perphenazine, flupenthixol or zuclopentixol (controls,n=100) were evaluated for extrapyramidal side effects (EPS) (blind) as well as other side effects and mental condition (non-blind). In both groups the patients had received neuroleptic treatment for a total of 14 years (median) and the present antipsychotic (clozapine or control drug) for 5 years. Thus the clozapine-treated patients had previously received traditional neuroleptics for 9 years (median). The study was both retrospective (0.3–19 years for clozapine, 0.3–24 years for control drug, by means of chart information) and prospective (1 year, with video-controlled evaluation of EPS). There was a significantly lower prevalence of tardive dyskinesia (TD) in clozapine treated patients than control patients, although prior to this treatment there were more TD patients in the clozapine group (P<0.05). This lower level of TD in the clozapine group was related to a lower induction of new cases (P<0.001) and a tendency towards greater disappearance of TD in the clozapine than in the control group (P=0.07). Clozapine treated patients without TD had started clozapine and ceased traditional neuroleptics at an earlier age than those with TD. Parkinsonian signs were seen in 33% of the clozapine patients versus 61% of the control patients, mainly as hypokinesia; tremor in 3% versus 11% and rigidity in 0 versus 19%. Psychic akathisia was found in 14% versus 40% and motor akathisia in 7% versus 29% of the patients, all differences significantly in favor of clozapine. Clozapine treated patients also had less neuroleptic-induced emotional indifference and depression, but more autonomic side effects than controls.

Extrapyramidal symptoms during long-term treatment with antipsychotics: special focus on clozapine and D1 and D2 dopamine antagonists.

In schizophrenic patients in maintenance treatment, clozapine, compared to classic neuroleptics, induces relatively few extrapyramidal syndromes (EPS), especially less akathisia and tremor and usually no dystonia or rigidity. In patients with dyskinetic movements (acute or tardive) induced by other neuroleptics, clozapine may reduce or even remove dyskinesia or permit it to disappear. It cannot, however, be excluded that clozapine can induce dyskinesia in extremely rare cases, but it seems more likely that this is due to previous treatment with classic neuroleptics. The earlier clozapine is started, the less chance of development of dyskinesia.The low level of EPS with clozapine may be linked to the special receptor-binding profile of this drug: during treatment with therapeutic doses of clozapine, the level of D2 receptor blockade is too low (40% to 50% occupancy by positron emission tomography) to induce EPS, and the D1 receptor blockade (also 40% to 50% occupancy) has a lower EPS potential than D2 blockade. This binding profile may at the same time contribute to the special antipsychotic properties of clozapine. Other receptor affinities may contribute to the beneficial effect of clozapine in EPS and schizophrenia.

The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment.

The effects of dopamine D1 and D2 receptor agonists and antagonists were studied in eight Cebus apella monkeys previously treated with haloperidol for two years. SKF 81297 (specific D1 receptor agonist) induced oral hyperkinesia of variable intensity (P less than 0.01): some of the monkeys developed extreme lip smacking, tonque protrusions and licking movements while others developed only slight lip movements. A combined treatment of SKF 81297 with LY 171555 (full D2 receptor agonist) or SCH 23390 (D1 receptor antagonist) inhibited the oral hyperkinesia induced by SKF 81297 (P less than 0.01, P less than 0.02, respectively). Raclopride (D2 receptor antagonist) did not statistically change oral hyperkinesia (P less than 0.2), although five monkeys showed increased oral movements; most of these monkeys had pre-existing hyperkinesia. Treatment with SCH 23390 or raclopride resulted in an identical dystonic/cataleptic syndrome. SKF 81297 inhibited the dystonia induced by SCH 23390, while it did not significantly affect raclopride dystonia. The investigation indicates that oral dyskinesia may be related to an imbalance in D1 receptor and D2 receptor stimulation in favor of D1 receptors. The question now is whether D1 receptor antagonists, which may have antipsychotic potential, will produce tardive dyskinesia after long-term use.

Sodium vaiproate and biperiden in neuroleptic-induced akathisia, parkinsonism and hyperkinesia

ABSTRACT ‐ Fifteen psychiatric patients participated in a double‐blind cross‐over study of the effect of sodium valproate (a GABA mimetic drug), biperiden (an anticholinergic drug) and placebo in neuroleptic‐induced akathisia, parkinsonism and hyperkinetic movements. All patients had subjective and objective signs of akathisia, 11 had parkinsonism and 11 hyperkinesia, eight of which were tardive dyskinesia (TD) and three initial hyperkinesia. After a pretreatment washout period of 2 weeks, during which anticholinergic drugs, if any, were replaced by placebo, the patients were treated in three randomized periods of 4 weeks with sodium vaiproate, biperiden and placebo. Compared to placebo, sodium vaiproate (900–2400 mg/day, median 1700) had no significant effect on akathisia and parkinsonism, although akathisia was reduced in four patients (unchanged in 10 and increased in one) and parkinsonism was induced or aggravated in seven patients (unchanged in five and reduced in three). Sodium valproate, however, reduced hyperkinesia score (TD + initial hyperkinesia) from 1.6 to 1.2 (P < 0.05). Biperiden (6–18 mg/day, median 12) significantly reduced akathisia score from 1.4 to 0.6 (P < 0.01) and parkinsonism from 2.0 to 0.6 (P < 0.01), and increased TD score from 2.1 to 3.9 (P < 0.05). None of the drugs induced significant side effects. It is concluded that 1) sodium valproate has no significant effect on akathisia, but a slight beneficial effect in hyperkinetic movements, both TD and initial hyperkinesia, 2) sodium valproate may aggravate parkinsonism without necessarily aggravating akathisia, and 3) anticholinergic drugs like biperiden appear still to be the best treatment for akathisia.