Jan Balldin

Electroconvulsive therapy in Parkinson's syndrome with "on-off" phenomenon.

During long-term treatment with L-dopa in Parkinsons syndrome “on-off” phenomenon develops in many cases, often entailing considerable therapeutic problems. Decreased sensitivity in postsynaptic striatal dopamine (DA) receptors has been shown to occur in parkinsonian patients during long-term treatment with L-dopa. This has been suggested as one possible mechanism for development of the “on-off” phenomenon. In contrast to L-dopa treatment electroconvulsions have been shown to increase sensitivity in the DA receptors, when administered to animals. The antiparkinsonian effect of electroconvulsive therapy (ECT) was investigated in five parkinsonian patients with “on-off” phenomenon, with or without concomitant signs of mental depression. ECT was administered according to praxis in treatment of mental depression. Drug therapy, including L-dopa, was maintained on previously adjusted doses during and after ECT. A marked improvement in the parkinsonian symptoms as well as in the “on-off” phenomenon occurred in three of the patients, persisting for several months. The other two patients showed only slight and transient improvement. It thus seems that ECT may be useful as a supplementary treatment in parkinsonian patients with “on-off” phenomenon. The antiparkinsonian effect of ECT is probably mediated by increased sensitivity in postsynaptic DA structures.

No evident neuronal damage after electroconvulsive therapy

Electroconvulsive therapy (ECT) is regarded as one of the most effective treatments for major depressive disorder but has also been associated with cognitive deficits possibly reflecting brain damage. The aim of this study was therefore to evaluate whether ECT induces cerebral damage as reflected by different biochemical measures. The concentrations in the cerebrospinal fluid (CSF) of three established markers of neuronal/glial degeneration, tau protein (tau), neurofilament (NFL) and S-100 beta protein, were determined in nine patients who fulfilled DSM-IV criteria for major depression. CSF samples were collected before and after a course of six ECT sessions. The CSF/serum (S) albumin ratio reflecting potential blood-brain barrier (BBB) dysfunction was also determined at these time points. The treatment was clinically successful with a significant decline of depressive symptoms in all patients as assessed by the Montgomery-Asberg Rating Scale for Depression. Several patients had signs of BBB dysfunction and/or neuronal damage before the start of treatment. Levels of CSF-tau, CSF-NFL and CSF-S-100 beta levels were not significantly changed by ECT. Also the CSF/S albumin ratio was found to be unchanged after the course of ECT. In conclusion, no biochemical evidence of neuronal/glial damage or BBB dysfunction could be demonstrated following a therapeutic course of ECT.

Studies on duration of a late recovery period after chronic abuse of ethanol. A cross-sectional study of biochemical and psychiatric indicators.

A cross‐sectional study on patients with different abstinence time was performed to describe long‐time biochemical and psychiatric changes due to withdrawal from heavy alcohol abuse. Physical, neurological, psychiatric and biochemical parameters were measured in 70 patients with a withdrawal period ranging from 2–90 days. The various parameters changed over time in different manners. Fatigability, reduced sleep, reduced sexual interest, apparent sadness, hostility and global ratings of abstinence improved significantly with the duration of the recovery period. Symptoms related to brain hyperexitability such as fatigability, inner tension, insomnia and pains persisted for approximately 5 weeks. Of the biochemical parameters, the transaminases were normal in patients with more than 10 days of abstinence, while the levels of γ‐glutamyltransferase and HDL‐cholesterol remained high for longer periods. The essential fatty acid status, measured by the fatty acid composition of serum lecithin, appeared to be normal only in patients with long recovery time. MAO in platelets was significantly lower than in the controls. The highest values were seen in the early recovery phase, which may indicate a temporary increase. Since polyunsaturated fatty acids are important constituents of synaptic membranes and since platelet MAO may reflect brain MAO, we consider these co‐existing findings important in the interpretation of the psychiatric symptoms. The study demonstrated the existence of a subacute withdrawal syndrome lasting for 4–6 weeks.

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.

Further neuroendocrine evidence for reduced D2 dopamine receptor function in alcoholism

D2 dopamine receptor function, as assessed by growth hormone (GH) responses to apomorphine (APO; 0.18-0.24 mg i.v.), was investigated in 15 male alcoholics with reported long-term abstinence. Results from only nine subjects could be evaluated. These subjects had been heavy alcohol consumers for a mean of 15 +/- 10 years and had thereafter been abstinent for a mean of 7 +/- 6 years prior to the investigation. Eight male healthy subjects, all of whom were light social drinkers, were selected as controls. The maximum GH responses to APO were significantly lower in the alcoholics (5.8 +/- 5.8 mU/l) than in the controls (22.1 +/- 19.2 mU/l). This finding gives neuroendocrine evidence for reduced D2 dopamine receptor function in alcoholics with long-term abstinence.

Changes in dopamine receptor sensitivity in humans after heavy alcohol intake

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18–0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.

Predictors for improvement after electroconvulsive therapy in parkinsonian patients with on-off symptoms

The antiparkinsonian effect of electroconvulsive therapy (ECT) was investigated in nine parkinsonian patients with “on-off” phenomena. The patients were maintained on previously adjusted doses of antiparkinsonian drugs during and after ECT. Parkinsonian as well as mental symptoms were rated before and after treatment. Basal serum levels of prolactin (PRL) and growth hormone (GH) as well as apomorphine induced changes (0.24 mg i.v.) in these levels were investigated three days before start of treatment. Marked improvement of parkinsonian symptoms was seen in five patients. Two further patients showed slight improvement. The improvement persisted for 2–41 weeks. Improvement after ECT was found to correlate with age at the time of treatment and with duration of L-dopa therapy as well as the estimated life-dose of L-dopa. No correlation was found between improvement of parkinsonian symptoms and either scores of mental depression before treatment, basal serum levels of GH and PRL or apomorphine induced changes in these hormone levels. The investigation indicates that ECT is a valuable adjuvant in the treatment of a selected group of parkinsonian patients with “on-off” phenomena. Furthermore, the results support our earlier proposal that ECT increases the responsiveness in postsynaptic dopamine sensitive structures.

Do Alcohol-dependent Individuals with DRD2 A1 Allele Have an Increased Risk of Relapse? A Pilot Study

AIMS The TaqIA polymorphism of the dopamine D2 receptor (DRD2) gene has been extensively studied in relation to alcoholism, and the TaqI A1 allele appears to be over-represented in alcohol-dependent individuals. In a recent study, this allele has also been associated with a highly increased mortality rate in alcohol-dependent individuals. In the present study, we investigated whether the TaqI A1 allele of the DRD2 gene region was associated with a higher relapse rate in alcohol-dependent individuals. METHODS Adult women (n = 10) and men (n = 40) with a diagnosis of alcohol-dependence were recruited from two Swedish 12-step treatment units for alcoholism. Subjects were genotyped for the TaqIA polymorphism. On average, 1½ year after the end of the treatment program, subjects were re-interviewed by using the alcohol-related items from the Addiction Severity Index follow-up version. RESULTS Thirty-three (66%) subjects self-reported relapse and 17 (34%) abstinence during the follow-up period. Thirty-sex percent (18/50) were carriers of the A1 allele of the DRD2 gene region, and 64% (32/50) were non-carriers. Among the carriers of the A1 allele, 89% (16/18) reported relapse in contrast to 53% (17/32) in the non-carriers (P = 0.01; odds ratio = 7.1). CONCLUSION The present study is, to our knowledge, the first report of an association between the TaqI A1 allele and a substantially increased relapse rate. It should be emphasized that the number of subjects is relatively small, and this investigation should therefore be considered as a pilot study.

Guanfacine as an alpha-2-agonist inducer of growth hormone secretion--a comparison with clonidine.

Doses of 0.5 mg and 1.0 mg of the alpha-2-adrenoceptor agonist guanfacine (GUA) and NaCl were administered intravenously (IV) in a randomized order to 18 healthy male subjects. GUA induced growth hormone (GH) secretion in a dose-dependent manner without affecting blood pressure or heart rate or inducing sedation. The effects of GUA 1.5 mg i.v. was compared with those of another alpha-2-adrenoceptor agonist, clonidine (CLON) 150 micrograms i.v. in six other male volunteers. Both alpha-2-agonists increased GH to similar levels. CLON reduced both systolic and diastolic blood pressure levels, whereas GUA reduced only systolic levels. Sedation was significantly more pronounced after CLON. The results suggest that the GUA/GH-test (1.5 mg GUA i.v.) may be an alternative to the CLON/GH-test in neuroendocrine assessment of alpha-2-adrenoceptor sensitivity.

Regulation of the Hypothalamic‐Pituitary‐Adrenal Axis in Dementia Disorders

In 163 patients with dementia disorders, subdivided into Alzheimers disease with early onset (AD; n = 40), senile dementia of the Alzheimer type (SDAT; n = 56), vascular dementia (VAD; n = 45) and dementia of unspecified type (NUD; n = 22) the dexamethasone suppression test (DST) was performed. The patients were rated according to the DSM-III-R criteria as having mild, moderate or severe dementia and were also assessed using the GBS scale which gives a profile of the dementia syndrome. In the total group of dementia there were significant correlations between severity of dementia and post-DST levels. The frequency of pathological DST also correlated significantly with the severity of dementia. In the subgroups of dementia a strong correlation between severity of dementia and high post-DST cortisol levels was found only in the VAD group. Between the subgroups of dementia disorders there were no significant differences in basal cortisol levels. The percentage of pathological DST was lowest in the AD group (40%). It was somewhat higher in the VAD group (49%), still higher in the SDAT group (54%) and highest in the NUD group (59%). When the relationship between post-DST cortisol levels and GBS scores was analyzed, significant correlations were found mainly in the VAD group. There intellectual impairment, anxiety, fear-panic and restlessness correlated significantly with post-DST cortisol levels. The results indicate hypothalamic overactivity in a substantial number of demented patients. In VAD and to a certain extent also in SDAT a disconnection between cortical areas, including the hippocampus, and the hypothalamus is assumed. Overactivity in the hypothalamic-pituitary-adrenal (HPA) axis is due to stress, and an insufficient feedback system leads to chronic stress adaptation failure.