Kjell Modigh

Clomipramine effectively reduces premenstrual irritability and dysphoria : a placebo-controlled trial

Forty nondepressed women displaying severe premenstrual irritability and/or dysphoria and fulfilling the DSM‐III‐R criteria of late luteal phase dysphoric disorder were treated daily for 3 menstrual cycles with either the potent serotonin reuptake inhibitor clomipramine (25–75 mg; flexible dosage) (n= 20) or placebo (n= 20). In both treatment groups premenstrual irritability and dysphoria (as rated daily by the patients using a visual analogue scale) were significantly reduced as compared with the rating during 2 pretreatment reference cycles; however, in the placebo group this reduction was only about 40% whereas, in the clomipramine group, the symptom decrease was >80%. At all 3 treatment cycles, patients on clomipramine displayed significantly lower symptom rating than controls. Also with respect to the rating of global improvement, the results obtained with clomipramine were considerably and significantly better than those obtained with placebo. It is concluded that low doses of clomipramine effectively reduce premenstrual irritability and dysphoria with a response rate close to 100%. The possible role of serotonin in the pathophysiology of the premenstrual syndrome is discussed.

Serum levels of androgens are higher in women with premenstrual irritability and dysphoria than in controls

Serum levels of progesterone, total testosterone, free testosterone, androstenedione (A2), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone binding globulin (SHBG) were measured in the follicular phase, around ovulation, and in the luteal phase of 11 women with severe premenstrual irritability and dysphoria and in 11 age-matched controls with no premenstrual complaints. Serum levels of free testosterone were significantly higher in the subjects with premenstrual syndrome (PMS) than in the controls in the luteal phase (p < 0.01), the follicular phase (p < 0.05), and around ovulation (p < 0.01). DHEA levels were significantly higher in the PMS subjects, as compared to controls, around ovulation (p < 0.05), while 17-OHP levels were higher in the PMS women in the luteal phase (p < 0.05). With respect to the other steroids measured, as well as SHBG, no differences between PMS subjects and controls were found. These results indicate a possible involvement of androgens in the pathophysiology of premenstrual irritability and dysphoria.

A double-blind evaluation of electroconvulsive therapy in Parkinson's disease with “on-off” phenomena

Abstract Eleven patients with severe Parkinsons disease and on‐off‐phenomena were included in a controlled double‐blind study on the effect of electroconvulsive therapy (ECT). Pharmacological treatment was optimally adjusted before the trial. The severity of extrapyramidal symptoms was measured before, during and after the treatment. The patients were randomly allocated into one group, receiving active ECT and another, receiving sham treatment. The patients given active ECT showed significantly (P < 0.05) prolonged duration of “on”‐phases after ECT, in comparison to the sham‐treated group. When collecting data from the controlled part of the study and the subsequent with open administration of ECT, the treatment was in addition found to significantly decrease the time and number of steps required to walk 10 meters. Moreover it reduced the severity of parkinsonian symptoms according to the Webster scale. The improvement induced by ECT was generally short‐lasting. Lumbar punctures were performed before and after ECT. The concentrations of mcnoamine metabolites in cerebrospinal fluid were not affected by the treatment. The results indicate that ECT has an antiparkinsonian effect which probably is mediated via changed responsiveness of dopamine receptors and that further improvement is possible in patients, therapy resistant to the presently available medication.

Evidence for a Growth Hormone Releasing Factor Mediating Alpha-Adrenergic Influence on Growth Hormone Secretion in the Rat

The effects of adrenergic receptor agonists on GH secretion were studied in adult, male rats pretreated with reserpine and somatostatin antiserum. Frequent blood samples were obtained from intra-aortic cannulae. Plasma GH was determined by radioimmunoassay. Reserpine (10 mg/kg i.p.) caused a complete suppression of the normal, pulsatile secretion of GH in all animals. Administration of somatostatin antiserum resulted in rapid elevations of plasma GH in reserpine-pretreated rats with peak levels at 30 min. GH levels then fell but remained slightly elevated for the duration of the sampling period (8 h). Apomorphine (0.5 mg/kg i.p.) had no effect on plasma GH levels, whereas clonidine (0.5 mg/kg i.p.) induced release of GH in both antiserum treated and control rats. The results indicate that the alpha-adrenergic influence on the secretion of GH is mediated not by inhibition of somatostatin release but rather by effects on the release of a GHRF.

Neuroendocrine evidence for increased responsiveness of dopamine receptors in humans following electroconvulsive therapy

The previous finding that electroconvulsive therapy (ECT) enhances effects of dopamine (DA) agonists was further investigated in the present clinical experiment using neuroendocrine techniques. Apomorphine chloride (AP) (0.18–0.24 mg IV) induced stimulation of growth hormone (GH) and suppression of prolactin (PRL), as shown 2–3 days before and after ECT in mentally depressed patients (N=12) and therapy-resistant parkinsonian patients with on-off phenomena (N=9). AP-stimulated GH secretion was not significantly affected by ECT, whereas AP-induced suppression of PRL, expressed as percentage of baseline PRL levels, was significantly enhanced after ECT. Changes in clinical and hormonal parameters were not significantly correlated. Control patients not receiving ECT showed no significant changes in AP-induced GH secretion or PRL suppression in repeated investigations. The results support the view that ECT increases responsiveness of DA receptors and indicates that AP-induced suppression of PRL is a useful model to reflect these changes in humans.

Up- and down-regulation of central postsynaptic α2 receptors reflected in the growth hormone response to clonidine in reserpine-pretreated rats

The α-adrenergic mechanisms exert a stimulatory influence on the secretion of growth hormone (GH) in the rat. In the present study the α receptors involved in GH regulation were characterized with respect to subtype. It was also investigated whether the GH response to α receptor agonists can be utilized to assess changes in the responsiveness of central α receptors. The experiments were performed on rats with implanted intra-aortic cannulae allowing frequent blood sampling from freely moving animals. Plasma GH was determined by radioimmunoassay. Reserpine (10 mg/kg) caused a suppression of the normal pulsatile secretory pattern of GH. The α receptor agonist clonidine (CLON) given to reserpine-pretreated animals induced a dose-dependent increase in plasma GH. The effect of CLON (0.2 mg/kg) was prevented by pretreatment with the α2 receptor antagonist yohimbine (3 mg/kg), but not by the α1 receptor antagonist phenoxybenzamine (10 mg/kg). Chronic pretreatment with CLON or imipramine, either of which can be expected to produce a reduced sensitivity of central α2 receptors, resulted in reduced GH responses to CLON. On the other hand, chronic treatment with yohimbine, which should cause denervation supersensitivity of α2 receptors, led to enhanced GH responses to CLON. The results indicate that GH release in the rat is stimulated by postsynaptic α2 receptors. They also suggest that the GH response to CLON can be used as a valid in vivo model reflecting decreased, as well as increased responsiveness of this type of receptor.

Effect of clomipramine on premenstrual syndrome.

Clomipramine (25–50 mg) was administered daily for 5 consecutive menstrual cycles to 5 nondepressed women with severe premenstrual irritability and sadness. All subjects reported a dramatic reduction in premenstrual complaints.

Superiority of Clomipramine over Imipramine in the: Treatment of Panic Disorder

A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.

Dopamine receptors involved in prolactin secretion pharmacologically characterized by means of 3-PPP enantiomers

3-(3-Hydroxyphenyl)-N-n-propylpiperidine (3-PPP) is a novel compound existing in two enantiomers which, as judged by recent biochemical and behavioural studies, both have clearcut though differential effects on central dopamine (DA) receptors. Thus, while both enantiomers act in low doses as agonists preferentially on autoreceptors, in higher doses the (+)-form is an agonist also postsynaptically while the (-)-form acts as an antagonist on postsynaptic DA receptors in the striatum and in the limbic system. In the present study both enantiomers were evaluated with respect to their effects on pituitary DA receptors involved in prolactin release. In previously untreated rats, no increase in prolactin release was observed after administration of either enantiomer in low or high doses. The lack of effect of high doses of the (-)-form indicates that DA receptors on the lactotrophs are pharmacologically different from postsynaptic DA receptors in nigrostriatal and mesolimbic systems. The finding that both enantiomers exerted a dose-dependent prolactin suppressive effect in reserpine-pretreated animals suggests instead that DA receptors on the lactotrophs are pharmacologically similar to DA autoreceptors in the brain. The effect of both 3-PPP enantiomers on prolactin release in reserpine-pretreated animals was antagonized by haloperidol, sulpiride and metoclopramide while pimozide and clozapine appeared less active. This finding is discussed with respect to possible selectivity on pre- vs. postsynaptic DA receptors for various antagonists.

Heart rate variability in premenstrual dysphoric disorder

Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.