Richard P. Ebstein

Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients

Serum and cerebrospinal fluid (CSF) levels of haloperidol were measured in 12 chronic neuroleptic-non-responsive schizophrenic patients after 1 month on 60 mg haloperidol daily and then again after 1 month on 120 mg haloperidol daily. Serum haloperidol and CSF haloperidol rose with increasing dose. Serum and CSF levels were significantly correlated. No clinical improvement was achieved despite the high serum and CSF drug levels.

Effect of lithium on the physostigmine-induced behavioral syndrome and plasma cyclic GMP.

Abstract Physostigmine has been reported to induce a syndrome of psychomotor retardation and in some cases a depressive syndrome. We attempted to investigate a possible mode of action of lithiums proven prophylactic value in depression by assessing the effect of pre-treatment with lithium on this physostigmine-induced behavioral response. A marked physostigmine response was observed in 5 lithium-treated, euthymic manic-depressive subjects as well as in 5 lithium-free, normal controls, with no diminution in the lithium-treated subjects. Plasma cyclic GMP, a possible product of cholinergic receptor activity, also showed no differential response in lithium-treated and lithium-free subjects.

Dopamine receptor changes after long-term haloperidol treatment in rats.

Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits & Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans & Rubovits 1972; Moore & Thornburg 1975; Sayers et al 1975; Tarsy & Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H‐neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller & Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.

Subsensitivity of human β-adrenergic adenylate cyclase after salbutamol treatment of depression

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct β-adrenergic receptor agonists have only recently been tested in the treatment of depression. Moreover, newer theories of antidepressant action suggest that a reduction in β-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. Eleven depressed patients were treated with salbutamol, a β-2-adrenergic agonist, and β-2-adrenergic receptor sensitivity was evaluated before, during, and after treatment. β-Adrenergic receptor sensitivity was evaluated by measuring the plasma cyclic AMP increase after an IV dose of salbutamol. The β-adrenergic agonist exhibited antidepressant efficacy and induced subsensitivity of the β-adrenergic adenylate cyclase with a time course paralleling the antidepressant effects. The results support the concept that receptor sensitivity changes occur during antidepressant therapy.

The differential effect of lithium on noradrenaline- and dopamine-sensitive accumulation of cyclic AMP in guinea pig brain.

Lithium (Li) in its narrow therapeutic concentration range was found to inhibit only the noradrenaline- and not the dopamine-sensitive accumulation of cyclic AMP in guinea pig brain. The results suggest a pharmacological distinction between the antischizophrenic drugs that inhibit dopamine-sensitive cyclic AMP accumulation and Li, an antimanic agent that inhibits specifically only the noradrenalinesensitive cyclic AMP accumulation.

Haloperidol and lithium blocking of the mood response to intravenous methylphenidate.

Ten euthymic manic-depressive patients with therapeutic plasma lithium levels were each given two i.v. infusions of 30 mg of methylphenidate. The infusions were separated by at least 3 days. Before one infusion each patient was given 5 mg of haloperidol i.v. and before the other infusion each was given an identical volume of saline. A psychiatric observer was blind to the nature of the pretreatment and the order of pretreatment was randomized. Saline pretreated patients showed marked activation and euphoriant responses despite therapeutic lithium levels. Haloperidol pretreatment reduced this response in three patients and eliminated the euphoriant and activating response in the remaining seven patients. These results agree with the existence of a dopaminergic step in the induction of methylphenidate-induced activation and euphoria.

Cyclic GMP in the CSF of patients with schizophrenia before and after neuroleptic treatment

Cerebrospinal fluid (CSF) cyclic GMP may derive from central cholinergic neurotransmission. Measurement of CSF cyclic GMP may allow evaluation of possible implications of the dopaminergic hyperactivity in schizophrenia proposed by the dopamine hypothesis. The CSF cyclic GMP levels in 27 drug-free schizophrenic patients was measured and compared to that in 9 psychiatrically-healthy individuals. The mean CSF cyclic GMP level of the schizophrenic patients was 23% lower than that of the control group, but this difference, did not attain statistical significance. In addition the CSF cyclic GMP levels in a group of 10 schizophrenic patients were compared before and after 2 months of neuroleptic treatment. The mean level of cyclic GMP rose 50% after treatment with phenothiazines (P<0.05). These results could indicate some tendency for decreased activity of central cholinergic neurons in schizophrenia as well as a restored dopaminergic-cholinergic balance after neuroleptic treatment.

Chronic lithium prevents reserpine-induced supersensitivity of adenylate cyclase

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The effect of l-dopa and propranolol on human CSF cyclic nucleotides

Human CSF cyclic AMP and cyclic GMP have been measured as possible indicators of activity of central neurotransmitter-sensitive adenylate or guanylate cyclase. In an attempt to help to identify the specific neurotransmitter systems of origin of human CSF cyclic AMP and GMP, we studied Parkinson patients with and without l-dopa therapy and schizophrenic patients before and after propranolol therapy. No effect of l-dopa or propranolol was found on CSF cyclic nucleotides. However, Parkinson patients had a 40–50% reduction of CSF cyclic AMP and a 80–90% reduction of CSF cyclic GMP compared with the schizophrenic patients. Implications of this finding are discussed.

Lithium inhibition of the adenosine-induced increase of adenylate cyclase activity

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