Hm Vanpraag

About the impossible concept of schizophrenia.

Abstract Schizophrenia is an impossible concept. It is used to summarize a group of psychoses that have in common the symptom that consciousness usually (not even always) remains unclouded during their course. No other common characteristics have been demonstrated in terms of symptomatology, etiology, or prognosis. There are, therefore, hardly any sound reasons to bring these syndromes under a single common denominator, such as “schizophrenia,” or to refer to them as a “group of schizophrenic psychoses.” It seems more likely that schizophrenic psychoses are separate entities, not variants of one basic form. What we need above all at this time is empirical research in an effort to chart the schizophrenia concept. Such a charting effort would have to start with carefully defined syndromes and should then investigate whether, apart from symptoms, there are other features that characterize a particular syndrome, e.g., etiology, pathogenetic factors, course, or response to therapy. The more such characteristics can be found, the greater the chance that we are dealing with a separate entity. Pending such studies, and in order to avoid terminological chaos, it seems advisable for the time being to maintain the term “schizophrenic psychoses” for practical purposes, provided that the designation in each actual case be supplemented with an accurate profile of the symptomatology, etiologic factors, and course.

The influence of probenecid on the metabolism of serotonin, dopamine and their precursors in man

Probenecid inhibits the efflux of acid monoamine (MA) metabolites from the CNS. The probenecid-induced accumulation of these metabolites in the CSF in man supplies data on the central turnover of the corresponding amines. In this study an attempt was made to establish whether probenecid also exerts an influence on the metabolism of the MA precursors: tryptophan and tyrosine. The principal conclusions were the following.1.Whereas in rats probenecid lowers the serum tryptophan level and elevates that in the brain (probably as a result of interference with the binding of tryptophan to serum albumins), the serum tryptophan level in human individuals is also lowered but the CSF concentration remains unchanged. After an oral tryptophan load, however, the CSF tryptophan concentration does increase.It is suggested that in man, endogenously released and exogenous tryptophan enter different metabolic pools in the brain.2.After an oral load of 1-tryptophan, for the most part depressive patients showed a more rapid increase in CSF tryptophan concentration and a less marked rise of the CSF 5-HIAA level than did the psychologically undisturbed test subjects examined by Eccleston et al. It seems possible that, in the depressive patient, the tryptophan-metabolizing capacity is disturbed.3.After an oral load of 1-tryptophan the CSF HVA concentration increased. Possibly, tryptophan is transformed to 5-HT in dopaminergic neurons, and this 5-HT may supersede the DA from the storage sites. This effect may well be of significance in the therapeutic application of 5-HT precursors.4.The CSF concentrations of 5-HIAA, HVA, tryptophan and tyrosine show no systematic variations during the day.

Determination of clomipramine and desmethylclomipramine in plasma by means of liquid chromatography.

A method is presented for the determination of clomipramine and its major metabolite desmethylclomipramine in plasma. After extraction with n-hexane, the components are separated by high performance liquid-solid chromatography on silica gel and detected with a UV detector. The detection limits are 2 ng/ml for clomipramine and 10 ng/ml for desmethylclomipramine. Recoveries from plasma exceed 95% for both drugs. In routine analysis, 30-40 samples can be handled in one day. The practical use of the method is shown in plasma concentration-time curves after oral and intramuscular administration of clomipramine.

Parkinson’s Disease and Amine Metabolites in Cerebrospinal Fluid: Implications for L-Dopa Therapy

Levels of homovanillic (HVA), 5-hydroxyindoleacetic acid and probenecid in cerebrospinal fluid were estimated in 42 patients with Parkinson’s disease undergoing the probenecid test. Relationship of the levels of amine metabolites and the serverity of the illness and the improvement after L-dopa therapy were established. One group of patients was treated with L-dopa alone, while the other was treated with L-dopa in combination with a peripheral decarboxylase inhibitor. We found a very high correlation between the HVA levels and improvement after L-dopa therapy in patients with relatively high levels of the dopamine catabolite. Patients with normal HVA levels in the cerebrospinal fluid did not respond to L-dopa. Also patients with extremely low HVA levels did not respond to L-dopa in a predictable way. Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid was related to the pretreatment severity of illness. The present results suggest that the effec-tivity of L-dopa therapy is related in part to the deficiency of the central dopamine-containing system, while 5-hydroxytryptamine is also involved in Parkinson’s disease. With the probenecid test it is possible to predict L-dopa therapy failure only in those patients with relatively high HVA levels in lumbar cerebrospinal fluid.

5-HYDROXYTRYPTOPHAN AS AN ANTIDEPRESSANT - PREDICTIVE VALUE OF PROBENECID TEST

The results of this preliminary study suggest that in depressions, the probenecid test is of predictive value with regard to efficacy of treatment with 5-hydroxytryptamine (5-HT) precursors. Although the number of patients investigated is small, the results do suggest that 5-hydroxytryptophan (5-HTP) benefits depressed patients showing a subnormal cercbrospinal fluid 5-hydroxyindoleacetic acid response to probenecid. The relevant implications of these data are that: a) 5-HT deficiency is etiopathogenic in some depressions; b) the probenecid test can be of diagnostic value in such patients; and c) 5-HT precursors, specifically 5-HTP, may be an effective treatment modality in such individuals.

Thyrotropin releasing hormone (TRH) as a possible quick-acting but short-lasting antidepressant

In a double reversal design the potency of thyrotropin releasing hormone (TRH) (500 mug intravenously) as a quick-acting antidepressive agent was evaluated. A first injection did seem to give rise to a very slight short-lasting effect, though this could not be ascertained clearly. There were no visible effects after a second injection. The thyroid stimulating hormone (TSH) response curve after TRH administration in the depressive patients group was blunted in comparison with that in a matched control group of normals.

Evidence for a probenecid-sensitive transport system of acid monoamine metabolites from the spinal subarachnoid space

The location of probenecid-sensitive elimination mechanisms of monoamine metabolites from the cerebrospinal fluid of the cat was determined with ventriculo-cisternal or ventriculo-lumbar perfusion techniques. These techniques were described in detail. Levels of endogenous homovanillic acid and 5-hydroxyindoleacetic acid were assayed in the perfusate. Probenecid administration induced the most marked increase of the levels of the monoamine metabolites in the ventriculo-lumbar perfusates. It was concluded that probenecid blocked the transport of both metabolites from the spinal subarachnoid space.

TRH BY SLOW, CONTINUOUS INFUSION - ANTIDEPRESSANT

A slow, continuous infusion of 1000 mug TRH (thyrotropin releasing hormone) over a period of 4 h had a very faint and diffuse short-lasting beneficial effect on a group of 10 depressive patients. This was assessed in a double blind cross-over trial with placebo. The effect was of no therapeutic value. No difference was found between the depressive patients and a control group of normal subjects in TSH response, T3 resin uptake, T4 or free thyroxine index values as a consequence of the TRH infusion.

BIOCHEMICAL RESEARCH INTO PSYCHOSIS - RESULTS OF A NEW RESEARCH STRATEGY

A strategy is presented for biological psychosis research with neuroleptics acting as a point of crystallisation like antidepressants do in biological depression research.

THE THERAPEUTIC EFFECT OF SHORT‐TERM ORAL DIAZEPAM TREATMENT ON ACUTE CLINICAL ANXIETY IN A CRISIS CENTRE

The assumption that oral diazepam treatment (20 mg daily) during 5 days in combination with active in‐patient crisis intervention has a favourable effect on acute clinical anxiety states was examined. A simple double‐blind random placebo‐diazepam design was applied on 30 crisis‐patients. The clinical improvement is defined as a difference‐score in ratings based on psychiatric interviews and ward observation.