Post Rm

The place of anticonvulsant therapy in bipolar illness

Abstract With the increasing recognition of lithium’s inadequacy as an acute and prophylactic treatment for many patients and subtypes of bipolar illness, the search for alternative agents has centered around the mood stabilizing anticonvulsants carbamazepine and valproate. In many instances, these drugs are effective alone or in combination with lithium in those patients less responsive to lithium monotherapy, including those with greater numbers of prior episodes, rapid-cycling, dysphoric mania, co-morbid substance abuse or other associated medical problems, and patients without a family history of bipolar illness in first-degree relatives. Nineteen double-blind studies utilizing a variety of designs suggest that carbamazepine, or its keto-congener oxcarbazepine, is effective in acute mania; six controlled studies report evidence of the efficacy of valproate in the treatment of acute mania as well. Fourteen controlled or partially controlled studies of prophylaxis suggest carbamazepine is also effective in preventing both manic and depressive episodes. Valproate prophylaxis data, although based entirely on uncontrolled studies, appear equally promising. Thus, both drugs are widely used and are now recognized as major therapeutic tools for lithium-nonresponsive bipolar illness. The high-potency anticonvulsant benzodiazepines, clonazepam and lorazepam, are used adjunctively with lithium or the anticonvulsant mood stabilizers as substitutes or alternatives for neuroleptics in the treatment of manic breakthroughs. Preliminary controlled clinical trials suggest that the calcium channel blockers may have antimanic or mood-stabilizing effects in a subgroup of patients. A new series of anticonvulsants has just been FDA-approved and warrant clinical trials to determine their efficacy in acute and long-term treatment of mania and depression. Systematic exploration of the optimal use of lithium and the mood-stabilizing anticonvulsants alone and in combination, as well as with adjunctive antidepressants, is now required so that more definitive treatment recommendations for different types and stages of bipolar illness can be more strongly evidence based.

Opposite effects of high and low frequency rTMS on mood in depressed patients: relationship to baseline cerebral activity on PET.

BACKGROUND Optimal parameters of rTMS for antidepressant efficacy in general, or within patients, have not been adequately delineated. METHODS Using a double-blind, sham-controlled, cross-over design, 22 adult patients with treatment refractory major depression (n=9; bipolar disorder, depressed phase) were randomized to active rTMS (20-Hz or 1-Hz) or sham rTMS conditions and given 5 rTMS treatments per week for two weeks. Repetitive TMS was administered at 100% of motor threshold for 1600 pulses over the left prefrontal cortex using a figure-eight coil. Patients initially randomized to sham rTMS were then exposed to two weeks of active rTMS with each frequency under blinded conditions. Those who received active 20-Hz and 1-Hz rTMS were crossed over to the opposite frequency for two weeks. Improvement in Hamilton Depression ratings were assessed after each two-week treatment phase. PET imaging was used to evaluate the patients baseline absolute regional cerebral activity (blood flow and metabolism) as potential predictor of clinical response. RESULTS Changes in depression severity on 1-Hz and 20-Hz rTMS were inversely correlated. PET scans with baseline hypoperfusion (but not hypometabolism) were associated with better improvement on 20-Hz rTMS as predicted. LIMITATIONS The magnitude of the clinical change with either frequency at 100% motor threshold was not robust, and larger studies with higher intensities of rTMS for longer durations of time should be explored. CONCLUSIONS High and low frequency rTMS exerts differential effects on depressed mood within individual subjects. The brain activity predictors and correlates of an optimal antidepressant response to rTMS remain to be better defined.

EFFECTS OF 1-DESAMO-8-D-ARGININE VASOPRESSIN ON BEHAVIOUR AND COGNITION IN PRIMARY AFFECTIVE DISORDER

DDAVP (1-desamino-8-d-arginine vasopressin), a synthetic analogue of vasopressin with prolonged half-life and high antidiuretic and low pressor activity, was given in a double-blind placebo-controlled trial to four patients with major affective illness. Three of four patients showed highly significant and consistent improvements in tests designed to measure the formation, encoding, and organisation of long-term trace events in memory. Two patients also showed a significant but less consistent amelioration of other depressive symptoms during DDAVP treatment. These findings implicate central vasopressin function in the processing of information and possibly other aspects of affective illness.

REM inhibitory effect of L-dopa infusion during human sleep

Abstract l -DOPA (25–50 mg) acutely inhibited REM sleep when infused intravenously during sleep in ten depressed psychiatric patients pretreated with a peripheral decarboxylase inhibitor (MK-485 or MK-486). Pre-REM infusions of l -DOPA delayed the onset of REM sleep while infusions at REM onset shortened the length of the REM period. These data are consistent with the hypothesis that catecholamines suppress REM.

Anticonvulsant withdrawal‐emergent psychopathology

We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.

Felbamate monotherapy has stimulant-like effects in patients with epilepsy ☆

The objective of this study was to assess the psychiatric effects of the antiepileptic drug (AED) felbamate (FBM) in patients with epilepsy. FBM is a new AED with a novel putative (antiglutaminergic) mechanism. Older AEDs such as carbamazepine and valproate have psychotropic properties, but the psychiatric effects of FBM and other new antiglutamatergic AEDs remain to be determined. Thirty inpatients with refractory epilepsy were openly tapered off all AEDs in conjunction with intensive presurgical monitoring prior to a two week randomized double-blind parallel trial of FBM monotherapy versus placebo, followed by open FBM therapy. Psychopathology was rated with weekly psychiatric rating scales. Anxiety, depression and seizures increased significantly with AED discontinuation. Acute blind FBM monotherapy yielded antiepileptic and stimulant-like effects (insomnia, anorexia, and anxiety), but failed to influence AED withdrawal-emergent psychopathology. Restarting original AEDs resolved such pathology in FBM drop outs. Chronic open FBM also had stimulant-like effects, with half of the patients displaying psychiatric deterioration and the other half modest improvement compared to baseline therapies. Baseline insomnia and anxiety may be markers for poorer psychiatric responses to chronic open FBM. FBM had stimulant-like effects, lacked anxiolytic effects, and failed to attenuate AED withdrawal-emergent psychopathology. Baseline insomnia or anxiety may predict poorer psychiatric responses to FBM. Further studies are required to assess whether the novel psychiatric effects observed with FBM also occur with other new antiglutamatergic AEDs.

The effect of orally administered cocaine on sleep of depressed patients

Cocaine was administered orally on a double-blind basis to depressed patients and effects on EEG-monitored sleep were assessed. In doses which did not produce consistent effects on vital signs or mood, cocaine significantly reduced total sleep and rapid eye movement (REM) sleep. The REM sleep supression with cocaine administration and rebound upon cocaine discontinuation was dose related; there was a greater effect at higher doses. Two properties of cocaine appear to closely correspond to those of many other drugs which suppress REM sleep in man—enhancement of functional catecholamines and/or high drug-abuse potential.

Slow and rapid psychobiological alterations in a manic-depressive patient: clinical phenomenology.

A distinctive pattern of clinical change during eight affective episodes is reported in a rapidly cycling manic-depressive patient. After a rapid switch to near maximal intensity of affective symptoms, slow changes in symptomatology were documented by significant slopes and correlation coefficients over the course of each episode. Decreases in depression, anxiety, drowsiness, helplessness/hopelessness, anger, and sadness preceded the switches into mania; decreases in mania, euphoria, seeking others, and talking preceded the switches into depression. Psychologically important events appeared to regularly precede rapid mood switches. It is suggested that the consistent, slow clinical changes which occur during affective episodes may reflect part of an underlying rhthmic biological process and that environment events may be capable of triggering a final common pathway for the mood switch during a vulnerable period.

Relationship of response to sleep deprivation and carbamazepine in depressed patients

ABSTRACT– The responses of 16 patients with major depressive disorder to one nights sleep deprivation and a subsequent double‐blind, placebo‐controlled trial of carbamazepine were compared. There was a significant association between the presence or absence of an antidepressant response to each of these treatments. Further studies are required to assess the clinical utility of this relationship and whether it is based on antidepressant response to any agent or is more specific to carbamazepine.

Cerebrospinal fluid amine metabolites in affective illness

is highly sensitive to fluctuations in dopaminergic activity. Growth Hormone (GH) is regulated by Growth Hormone Releasing Factor (GHRF) which appears to be in large measure adrenergically controlled. Corticotrophic Releasing Hormone (CRH) is also subject to monoaminergic control, particularly by serotonin and noradrenalin. Studies of neuroendocrine function in patients with schizophrenia and affective disorders thus offer an approach to testing the various hypotheses about altered biogenic amine metabolism in these conditions.