H. M. Emrich

The Use of Sodium Valproate, Carbamazepine and Oxcarbazepine in Patients with Affective Disorders

During recent years alternatives to lithium prophylaxis have been developed using primary dipropylacetamide and, later on, sodium valproate, as a mono-therapy as well as in combination with low-dosage lithium treatment. It has been shown in a placebo-controlled ABA design that sodium valproate exerts an acute antimanic effect and a prophylactic action of sodium valproate has also been established. Carbamazepine represents another important contribution to the arsenal of drugs to be used as alternatives for the prophylactic treatment in patients not responding to lithium and/or experiencing too many side effects. The keto-derivative of carbamazepine, oxcarbazepine, has been shown to exert acute antimanic effects in a similar way to carbamazepine itself.

Effect of sodium valproate on mania

SummaryA possible antimanic property of the GABA-ergic anticonvulsant valproate was examined by use of a double-blind placebo-controlled ABA design in 5 acutely ill manic patients. In 4 cases a marked improvement was observed after valproate medication whereas one patient showed no response. Seven further patients with frequently recurrent episodes of a manic or maniform schizoaffective psychosis, irresponsive to lithium prophylaxis, were chronically treated with valproate in combination with low doses of lithium (one case only with valproate). Over an observation period of 1 1/2–3 years none of the patients exhibited a relapse. It is proposed that, in general, GABA-ergic anticonvulsants possess antimanic properties and that the specific antimanic effect of lithium is due to a GABA-ergic mode of action. The possible role of GABA-systems in affective disorders and in organic types of psychoses (e.g., porphyria-psychosis, delirium tremens) is discussed on the basis of pharmacopsychiatric considerations.ZusammenfassungUnter Verwendung eines doppel-blinden ABA-Designs mit Placebo-Kontrolle wurde bei 5 Patienten mit akuter Manie eine mögliche antimanische Wirkung des GABA-ergen Anticonvulsivums Valproat untersucht. Bei 4 Patienten wurde eine deutliche Besserung beobachtet, während ein Patient auf Valproat nicht reagierte. Bei 7 weiteren Patienten mit häufig wiederkehrenden Phasen einer manischen oder maniformen schizoaffektiven Psychose, die auf die Lithium-Prophylaxe nicht ansprachen, wurde eine Dauerbehandlung mit Valproat in Kombination mit kleinen Lithium-Dosen durchgeführt. (In einem Fall wurde nur Valproat, ohne Lithium, gegeben.) Im Verlauf einer Beobachtungsphase von 1 1/2–3 Jahren wurde bei keinem dieser Patienten ein Rückfall beobachtet. Es wird die Hypothese vorgeschlagen, daß grundsätzlich GABA-erge Anticonvulsiva antimanische Eigenschaften aufweisen und daß auch der spezifische antimanische Effekt von Lithium auf einer GABA-ergen Wirkungskomponente beruht. Eine mögliche pathophysiologische Bedeutung zentraler GABA-Systeme bei affektiven und organischen Psychosen (z.B. Porphyrie, Delirium tremens) wird auf der Basis pharmakopsychiatrischer Überlegungen diskutiert.

Possible antidepressive effects of opioids: action of buprenorphine.

The euphorogenic and anxiolytic properties of opiates and of endorphins * prompt questions as to the possibility that a defectively operating endorphinergic system may represent a causative factor in the pathogenesis of endogenous depression. Though from biochemical and pharmacological data the evidence in support of this hypothesis is weak (cf. ref. 3) it, nevertheless, requires additional evaluation. However, irrespective of the presence of a hypothetical constitutional deficit of endogenous morphinomimetic substances compensated for by an exogenous supply in the therapy of depressed patients, the question arises if, independently from such a possible type of metabolic dysfunction in depression, there may exist direct pharmacodynamic therapeutic effects of opioids in depressive syndromes. Since anxiety and sleep disturbances, in addition to melancholia, make up an integral part of the psychopathology of depression, from their profile of action, it may be anticipated that opioids could be highly effective, therapeutically, in depressive illness. the “opium cure” has been recommended for the treatment of depressed patients, employing slowly increasing and later decreasing dosages of tinctura opii and of other opiates.B Interestingly, according to reports of that time, although a standardized evaluation of the therapeutic efficacy was, and is, lacking, this treatment was effective and did not result in opiate addiction, possibly, since the doses applied were comparatively low. Later, Fink et al.7 applied the mixed agonist/antagonist cyclazocine (1.0-3.0 mg) in 10 severely depressed patients and observed a strong antidepressive effect, in particular concerning the items “depressed mood” and “apathy.” A further clinical evaluation of possible beneficial effects of opiates has been deferred, possibly owing to the psychotomimetic effects of cyclazocine and, furthermore, in view of the fact that the discovery of tricyclic antidepressants and of MAO-inhibitors opened a new era in the pharmacotherapy of depressive syndromes. Interestingly, immediately after the discovery of the endorphins, which shed new light onto the possible psychotropic effects of an activation of opiate receptors, new attempts were initiated in the evaluation of the possible antidepressive effects of opioids. Kline et a1.* were the first to perform clinical trials in different types of psychiatric disorders (schizophrenia, depression, neuroses) by use of /3-endorphin infusions (1.5-6.0 mg) and observed in two depressed patients, in an open design, positive effects of this treatment. Angst et a1.,8 also in an open trial, investigated the possible antidepressive action of infusions of 10 mg of B-endorphin and detected a switch to hypomania/ mania in three of six depressed patients. Subsequently, doubleblind trials as to the possible antidepressant efficacy of &endorphin have been Indeed, since the time of Emil Kraepelin

Regional cerebral glucose metabolism in anorexia nervosa measured by positron emission tomography

Regional cerebral glucose metabolism was measured in five female anorectic patients, during the anorectic state and after weight gain, using the fluorodeoxyglucose method and positron emission tomography. In addition, these results were compared with those of 15 young male normals. During the anorectic state, significant caudate hypermetabolism was found bilaterally, unlike the finding in repeat measurements or in male normals. In some other brain structures (temporal cortex, lentiform nucleus, thalamus, and brainstem), significant hypermetabolism was also found during the anorectic state, but these results were not concordant for both sides and in both comparisons. There was no difference between patients after improvement and young male normals.

Carbamazepine as an adjunct of antipsychotic therapy

The effect of low-dose haloperidol combined with the anticonvulsant carbamazepine was investigated in a 5-week placebo-controlled, double-blind study in acute schizophrenic patients. Weekly ratings showed a clinically pronounced and statistically significant improvement in both the carbamazepine and placebo groups. However, the patients on carbamazepine needed less neuroleptic and anticholinergic medication and experienced fewer side effects compared to the patients on placebo. Moreover, patients in the carbamazepine group showed a clear deterioration after discontinuation of carbamazepine (but maintenance of neuroleptic medication), while the placebo group did not change after discontinuation of placebo. Concomitant treatment with carbamazepine in psychotic patients may help to reduce neuroleptic dosages and unwanted side effects.

Therapeutic effects of GABA-ergic drugs in affective disorders. A preliminary Report

A possible antimanic efficacy of the GABA-ergic anticonvulsant valproate was examined by use of a double-blind, placebo-controlled ABA design. A marked improvement was observed after valproate medication in a group of 5 acutely ill manic patients. Similar results were obtained in 7 trials examining the antimanic property of the keto-derivative of carbamazepine (oxcarbazepine) in 6 patients with acute mania, whereas no antimanic effect could be observed in a treatment with diazepam and with THIP. Combination of THIP and diazepam in another patient showed a slight antimanic effect. Additionally, a possible prophylactic effect of long-term treatment using valproate was examined. In 8 of 9 patients exhibiting a bipolar affective or schizoaffective psychosis, who did not properly respond to lithium treatment, a prophylactic effect of valproate medication could be demonstrated. The results point to the view that anticonvulsants, possibly due to GABA-ergic effects, may be beneficial in affective disorders.

Dopamine and the action of opiates: A reevaluation of the dopamine hypothesis of schizophrenia with special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia

It is suggested that the antipsychotic efficacy of opioids in patients suffering from schizophrenia may result from an interaction of opioids with the dopaminergic system. The modulatory effect of opioids on dopaminergic functions has already been demonstrated in basic experiments: Anatomical and biochemical data reveal an interaction between opioid receptors and dopamine (DA) actions on dopaminergic nerve terminals, cell bodies, and afferent nerve endings. Endogenous enkephalin levels correlate well with the endogenous dopamine content in various brain areas. Systemic or iontophoretic administration of morphine alters the spontaneous activity of ventral tegmental dopaminergic neurons. Morphine and enkephalin effectively enhance pituitary prolactin release, whereas dopamine inhibits it. Opioid agonists effectively alter DA release, DA reuptake, and DA metabolism in the striatum and substantia nigra. In reverse, chronic neuroleptic treatment enhances the synthesis and release of pituitary beta-endorphin. Opioids affect contralateral rotation elicited by dopamine agonists in animals with unilateral lesions of the nigrostriatal pathway. Phencyclidine, a psychotropic drug that shares certain pharmacological characteristics with the putative sigma-opioid receptor ligand SKF 10,047, indirectly mimics the effects of dopamine agonists on prolactin release, release of acetylcholine, etc. It is suggested that an imbalance of opiate-DA interaction might be involved in the pathogenesis of schizophrenia. Consequently, clinical studies on the effects of opioids on psychotic symptoms should also examine opioid influence on dopaminergic functions in these patients.

The effect of neuroleptic treatment and of high dosage diazepam therapy onβ-endorphin immunoreactivity in plasma of schizophrenic patients

In 14 schizophrenic patients, treated with neuroleptic drugs, and in 7 patients, treated with high-dosage diazepam,β-endorphin-like immunoreactivity in plasma has been measured by use of a highly sensitive and relatively specific radioimmunoassay. Neuroleptic treatment induced a significant increase ofβ-endorphin-like immunoreactivity (β-ELI). The pharmacological and clinical implications of this finding are discussed. High-dosage diazepam treatment induces a slight reduction of plasmaβ-ELI, a finding which is attributed to antistress effect of diazepam.

Endorphinergic Systems and the Response to Stress

Endogenous opioid peptides (EOPs) are extensively disturbed throughout the CNS and found in the CSF, pituitary, plasma and many peripheral organs of animals and man. Their intracerebroventricular administration produces a spectrum of morphinomimetic effects. Biochemical evidence for an acute stress-evoked release of brain, spinal cord and pituitary pools of EOPs has accumulated and the sensitivity of both adult and developing endorphinergic systems to chronic stress has been shown. EOPs are involved in the mediation of the elevations in nociceptive threshold, core temperature, exploration and grooming behaviour elicited by stress. A role in the attenuation of anxiety is also indicated. Finally an endorphinergic control of pituitary secretion and the activity of peripheral organs under stress has been demonstrated. EOPs are apparently of general importance in the response to stress in both animals and man.

Diurnal variation of mood and the cortisol rhythm in depression and normal states of mind

SummaryA large scale chronobiological investigation was undertaken in 20 drug-free psychiatric inpatients displaying RDC major depression (endogenous subtype) in comparison to 10 healthy control subjects and 10 of the patients after clinical recovery. A series of measurements was taken 6 times a day and, in 8 of a total of 14 variables, also once a night over a period of 10 to 14 days. The following variables were assessed: mood (three different scales), performance (two tests), motor activity (three measures), salivary flow, urinary excretion of water, sodium, potassium, and free cortisol (UFC), and rectal temperature. A phase chart of the acrophases of the 8 variables with measurements taken during day and night revealed two clusters in the depressives and three in the non-depressed subjects. In the depressives, the acrophases of the mood scales clustered around the time of awakening in the morning, together with the acrophase of UFC, whereas all other acrophases clustered in the afternoon. In the non-depressed subjects, however, the mood scales reached their circadian maxima in the middle of the night around the time when sleep was interrupted to take measurements. All other acrophases corresponded roughly with those found in the depressives. The coincidence of the time course of depressed mood and cortisol excretion in the patients was interpreted as reflecting a temporal relationship between diurnal mood swings in depression and the cortisol rhythm. This interpretation was supported by the significant correlation between the acrophases of the two respective rhythms in patients showing a significant diurnal variation in mood. The mood curves of non-depressed subjects seemed unrelated to the cortisol rhythm. Probably, they mirror diurnal fluctuations of vigilance rather than fluctuations of mood. According to the literature, this rhythm is temporally related to the rhythm of melatonin secretion.