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1992. Vol. 16. pp. 691-701

VALPROATE

TREATMENT

0278 - 5946/92 $15.00 e 1QQ2Rq@monF’rmUd

OF MANIA

HINDEBK M. EMBICH and RAINEB WOLF

Max Planck Institute of Psychiatry, Munich, Germany

(Final form, September 1991)

Emrich, Hiiderk M. and Bainer Wolf: Valproate-Treatment of Mania: Prog. Nemo-Psychopharmacol. & Biol. Psychiat. 1992, 16(5): 691-701. 1. Acute as well as prophylactic effects of the anticonvulsant valproate are described in patients with mania and bipolar affective psychoses. 2. In a long-term evaluation of valproate prophylaxis ranging up to 14 years, an average improvement of the phase chart of 12 patients was observed by a factor of 12. 3. The mode of action of this effect appears to be related to the GABAergic properties of the compound. Kevwords; anticonvulsants, GABA, mania, valproate Abbreviations: A=placebo; B=drug; A=placebo (ABA), conceptual disorganization (CNP); dipropylacetamide (DPA); excitement (EXC); grandiose expansiveness (GBN); hostility (HOS); International Classification of Diseases (ICD); Inpatient Multidimensional Psychiatric Scale (IMPS); luteinizing hormone (LH); luteinizing hormone releasing hormone (LHBH); motor disturbances (MTB); Verlaufs-Beurteilungs-Skala (VBS). Introduction Mania is a psychiatric syndrome which may appear to be very far from epilepsy. However, new therapeutic approaches to the treatment of special epileptic types of psychoses with affective symptoms have, historically, contributed a lot to the development of the treatment of endogenous affective psychoses with anticonvulsants. For example, the work of Takezaki and Hanaoka (1971), using carbamazepine in epileptic patients with symptomatology suggesting hypomania, led to the question as to whether also patients with endogenous mania might profit from such a therapy, and indeed these authors, and subsequently Okuma et al. (1973), could demonstrate such a therapeutic effect with carbamazepine. In the case of the anticonvulsant valproate, the first studies in endogenous affective disorders were not performed with valproate.itself, but by use of its amidation product, namely dipropylacetamide (i.e. valpromide). These investigations were performed by Lambert et al. as early as in 1966. In these studies the authors observed - besides the anticonvulsant efficacy - psychotropic effects in non-psychotic disturbances of mood, especially 691

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affective lability, impulsiveness,

M. Emrich and R Wolf

irritability, etc. Later on, Lambert et al. (1968) described therapeutic effects

of valpromide in patients with cyclothymia. However, it was only in 1975 (Lambert et al., 1975), that a more detailed description

of the effects of valpromide

in patients with affective disorders

was given. In these

observations it became apparent that valpromide had a mild antimanic, a slight antidepressant,

and - especially

in combination with low doses of lithium - a mood stabilizing effect in bipolar patients. Lambert et al. (1984) described, in a mixed group of a total of 244 cases with affective disorders,

108 cases with cyclothymia and

additionally 20 cases with mania and hypomania, who were treated with dipropylacetamide.

The therapeutic

effects were good or very good in 45 cases of cyclothymia and acceptable in 39 cases, whereas 24 of these 108 patients showed no therapeutic effect. In the 20 cases of pure mania or hypomania 7 patients showed a good or very gocd response, 9 a medium response, and 4 had no benefit from the treatment. Puzynski and Klosiewicz (1984) described 10 bipolar cases and 5 schixoaffective cases treated with valpromide. The prophylactic effect of valpromide was especially noticeable with regard to manic phases, where a total reduction in the order of magnitude of 50% was observed. McElroy et al. (1987) published a comprehensive overview of the use of valproate and valpromide in psychiatric disorders. These authors came to the conclusion that valproate represents a valuable addition to the therapeutic arsenal in the pharmacotherapy

of affective disorders. In their study they

demonstrate an acute effect of valproate in mania in more than 75 96 of 17 bipolar cases (cf. also additional recent findings by this group (Pope et al,, 1991)). The interest in the acute therapeutic effect of the GABAergic anticonvulsant pharmacopsychiatric

valproate was raised from

investigations studying the effect of high-dosage propranolol treatment in manic syndromes.

It was shown, using a double-blind ABA design, that high-dosage propranolol exerts a rather specific antimanic action (Rackensperger et al., 1976). Interestingly, it was possible to demonstrate that this effect is not mediated by B-receptor blockade, since the d-stereoisomer,

which is devoid of fl-receptor blocking properties, also has

similar antimanic effects (Emrich et al., 1979). The therapeutic action had been postulated by Delini-Stula, from animal experiments,

to be mediated by a GABAergic component of the propranolol

molecule (Vassout and

Delini-Stula, 1977). In line with this, Bemasconi et al. (1982) demonstrated an indirect GABAergic effect of high-dosage propranolol in viw. For that reason, the authors looked for other compounds which could clinically be applied to exert GABAergic effects in man. The first candidate in this regard was sodium valproate, a substance which is assumed to exert its anticonvulsant effect mainly via an indirect GABAergic mode of action (cf. Bemasconi et al., 1984). Preliminary positive results in this regard gave rise to the GABA-hypothesis

of

affective disorders (Emrich et al., 1980).

Methods Study Desien The patients acutely treated with valproate displayed a manic psychosis double-blind, placebo-controlled,

variable ABA design (A=placebo,

B=active

and were treated by use of a substance). The length of each

Valpmate treatment

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of manta

phase was unknown to the patient and to the psychiatrist avowing

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the psych~~logi~

evaluation.

Informed consent was obtained from both the patients themselves and their close relatives prior to ~rnrn~~rn~t of the trial. Psychopathological evaluation was performed by a physician using the Inpatient Multidimensional Psychiatric Scale (IMPS: Lorr et al., 1962). Five of the 12 IMPS subscales @XC, HOS, GRN, MTR, CNP) were summed to form a score reflecting the patient’s manic symptomatology. An extensive physical and neurological examination was performed in all patients prior to initiation of the trial. X-ray examinations were performed prior to onset of medication. Thrombocyte count and bleeding time, in particular, were controlled both before and during the course of medication. The maximum dosage ranged from 1.8 to 3.8 g/d.

Twelve patients, suffering from pure affective (ICD-9-Nos. 296.1; 296.3) or schixoaffective psychosis (ICD-g-No. 295.7) were included into the study @CD: International Classification of Diseases, 9th Rev. ) WHO, Geneva, 1978).

Long-term prophylactic medication with valproate (1200 f 300 mgld) (in one case with dipropylacetamide) @PA: 1200 f 300 mg/d) was given to 12 lithium non-responders, in 11 of them in combination with low doses of lithium (serum levels 0.4-0.8 mmoY1);in 1 case, discontinuation of the lithium treatment for some time was necessary owing to the uccm-rence of severe lithium side-effects. Assessments The clinical course of these outpatients was evaluated by a trained psychiatrist (open study), using the VRS (Verlaufs-Reurteilungs-&la,

i.e. course-assessment scale), a self-constructed scale with 8 degrees of intensity,

adapted here to reflect the global impression of “manic behavior” and “depression” (cf. Emrich et al., 1977). Data Analvsis Data were analyzed applying nonparametric statistics (Wilcoxon-test) to the phase-intervals and relapse-free times during treatment, derived from the phase-charts. Results and Discu&

Acute Effects of Vala An average reduction of the initial IMPS values by 49.6 f 36.6% resulted from this therapy (significant at the 5 %-level, Wilcoxon-test, one-tailed).

9

7

19 12 7 11 12 15 3

10

5

10

4

14.0 9.5 13.0 a.5 4.0 12.0 11.0 l.Sb 11.0 1.5b 10.0

'Relapsesonly of schizophrenicsymptom8 bDiscontinuation of therapyafter 1.5 years due to non-compliance 'Two relapsesafter 2 discontinuations due to non-compliance dOne relapseafter discontinuation due to non-compliance

DPA (+ low-dosagelithium) 12 59 m 296.2

Valproate(t low-dosagelithium) 1 56 m 296.3 2 40 m 295.7 3 49 m 295.7 4 66 m 296.3 5 42 f 295.7 6 34 f 295.7 7 70 f 296.1 a 43 f 296.3 9 35 m 295.7 10 35 m 295.7 11 36 m 296.3

0

0 6a 0 OC 2 3o 0 0 0 0 0

f 12.1 f 12.8

6.9

18.7 1.6 31.2 10.2 0.8 3.0 18.9 1.6 11.0 1.2 40.0

Case Age Sex Diagnosis Average intervalbetween Duration Number of relapse8of Improvement of the affectivedisorder ratio (ED-91 phases during the last (yrs) r 5 years before treatment therapy during therapy (months) (yrs)

Table 1 ClinicalCourse of Patientsunder Long-TermValproatelDPA-Therapy (1200 f 300 mg/d)

vatpruate treatmentofmanta

895

The clinical coursa of patients under long-term valproate therapy (mostly in ~mbi~ti~

with low li~ium

dosages) is represented in Table 1. The patients included in this long-term prospective investigation belong to a group of “problem cases” who did not respond adequately to lithium. The average interval between phases over the 5 years preceding valproate4DPA treatment ranged from 3 to 19 months, whereas the relapse-free tune during this treatment has ranged (up to the present) from 16 to 168 months. The most impressive therapeutic effects of valproate, used as adjunct to the lowered dosages of lithium, continuously applied to the patients, is also apparent from Figs. 1-2, which mpresent the phase-charts of selected patients. If the ,jrn~e~t

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1976

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1961

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ratio” t is defined as

*8 4 0 4 -

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-8 1972 +8 -

4 -8 L

1979

+8r

Fig. 1. Time course of the psychopathology of a patient with bipolar affective disorder (ICD-9, No. 296.3), represented by use of the VBS ~erlauf-~u~ilungs-Spa, i.e. ~~~~srn~t-~e; cf. Emrich et al., 1977) under prophylactic long-term medication with valproate in combination with low doses of lithium. Symbols: Heavy bars: hospitalization; +8 = maximal mania; -8 = maximal depression.

average phase interval (months) after treatment r= average phase interval (months) before treatment r = 1 would mean no effect; r < 1 deterioration; r > 1 improvement; r = 2 improvement by a factor of 2; r = 3 improvement by a factor of 3, etc.

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1967

1969

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1976

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1972

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1966

1966

1990

1965

Fig. 2. Time-course of the psychopathology of a patient with schixoaffective psychosis (ICD-9, No. 295.7). Symbols as in Fig. 1. Cross-hatched areas represent episode with admixture of schizophrenic symptoms.

In the 12 cases examined, the average improvement ratio is 12.1 f 12.8 (comparing the course of the illness during valproatiDPA prophylaxis with prior lithium prophylaxis). A statistical analysis was performed by a comparison of the average mean phase interval before valproate/DPA medication with the relapse-free time during this treatment (Table 2). The average values are: R = 10.0 f 4.3 months before, and X = 80.1 f 60.3 months during treatment. This difference is highly significant @ < 0.005, Wilcoxon test, two-tailed).

Valproatc treatmentof mania

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Table 2 ValproatelDipropylacetamide-Prophylaxis Phase interval prior to treatment (months)

9 10

5

10 19 12 7 11 12 15 3 7 E

f

10.0 4.3

Relapse-freetime during treatment (months) 168 16 156 102 15 36 132 18 132 18 120 48 go.1 60.3

p < 0.005 (Wilcoxon.2-tailed)

The most often cited hypothesis on the mechanism of action of valproate originated with Godin et al. (1969) and suggested that valproate augments neuronal inhibition by increasing brain levels of GABA via an inhibition of the GABA degrading enzyme GABA-transaminase. However, several objections to the increased-GABA-level hypothesis have been made: (a) the concentrations of valproate used by several authors were many times higher than the range of the therapeutic level for humans; (b) there was only a poor correlation between valproate-induced GABA levels in animal brain and the protection against chemically or electrically induced seizures (Schmutz et al., 1979; Kerwin et al., 1980); (c) it is not clear whether enhanced synaptic GABA concentrations lead to an increased GABA release into the synaptic cleft which might be necessary for enhanced GABAergic transmission; (d) concentrations of valproate up to 10 mM were shown to have no inhibitory effect on GABA-T (Liischer, 1980). A second hypothesis was proposed by Macdonald and Bergey in 1979, who demonstmted an enhanced responsiveness of cultured spinal cord neurons to iontophoretically applied GABA. Also direct membrane effects of valproate have been reported @later and Johnston, 1978). It was therefore of interest to investigate the action of valproate in therapeutic and higher concentrations on synaptic GABA release utilizing the push-pull-cannula technique, a method of focal in vivo-perfusion of brain structures, in unanaesthetized, freely moving rats. We chose the ovarectomized rat as an animal model in order to get an estrogen-cycle independent feedback situation of the hypothalamic-pituitary axis, and tried to reveal the

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M. JZmrtchand R Wolf

effect of preoptically applied valproate on this neuroendocrine network, since there seem to be several interrelations between valproate, GABA, and neuroendocrine functions. Preoptically applied sodium valproate, in a concentration range from 40 to 1600 pglml CSF, differently affected the local release of GABA into the push-pull perfusate. Local treatment with 40, 80, 100, and 200 pglml perfusion medium induced a highly significant decrease in preoptic GABA release (Fig. 3). After return to valproate-free medium this effect was reversible. A rapid onset and termination of the valproate effect within 5 min could be observed. Going higher with valproate concentrations the suppressive effect became less and at supra-therapeutic valproate levels of 1600 pglml CSF an increase. in GABA release could be observed in 4 out of 8 animals. This dose response relationship points to a biphasic effect of valproate on the available amount of

GABA in the synaptic cleft, which may be produced by at least two different dose-dependent mechanisms of action. The present results indicate that the action of therapeutic concentrations of valproate involves an alteration of GABAergic transmission different from increasing synaptic GABA release. Nevertheless, the data are

consistent with the hypothesis that valproate action, at least at the level of the preoptic area, involves an

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Fig. 3. Dose-response-relationship derived from a total of 51 rats, perfused with valproate at different concentrations (number of rats in parenthesis): O(8), 40(4), 80(8), lOO(5),2OO(6),4OO(6),8OO(6),16OO(8)pglml CSF, respectively. Ordinute:Mean percentage of intraindividual alteration of GABA release between the period under treatment (n = 8 fractions) compared with the period before treatment (n = 8 fractions). Mean values as circles with SEM as vertical bars are given. Abscissa (logarithmic scale): Concentrations of valproate per ml CSF. Asterisks: ***p