Withdrawal Depression in Obese Patients after Fenfluramine Treatment

Measurements of subjective feeling in 20 patients receiving fenfluramine alternating with placebo and in 19 patients receiving phentermine alternating with placebo indicated that depression of mood occurred four days after fenfluramine withdrawal but no such depression was seen with phentermine.     

Levodopa in Parkinsonism: the Effects of Withdrawal of Anticholinergic Drugs

The results are reported of a trial in which 34 patients receiving a stable dose of levodopa for the treatment of idiopathic Parkinsonism, as well as anticholinergic drugs which they had been taking before the introduction of levodopa, underwent withdrawal of their anticholinergic remedies. Withdrawal was gradual over four weeks in 17 patients (group 1) and abrupt in the remaining 17 (group 2).Only 11 out of 34 patients on stable levodopa therapy were able to tolerate withdrawal of anticholinergic drugs for more than eight weeks. The main reasons for the resumption of these remedies were subjective increases in slowness in 20 (59%), tremor in 15 (44%), and recurrence of hypersalivation in 5 (15%). Hypersalivation was the single feature which was most significantly and adversely influenced by anticholinergic withdrawal in patients on levodopa irrespective of whether withdrawal was sudden or gradual. It is suggested that the synergism which seems to exist between anticholinergic remedies and levodopa may be due to inhibition of dopamine inactivation by anticholinergic drugs, thus ensuring continual utilization, or alternatively, to a primary central anticholinergic effect.Objective and more severe subjective deterioration occurred only on sudden withdrawal. Hence we would advise that if for any reason anticholinergic drugs are to be withdrawn in patients receiving a stable dosage of levodopa this must be done slowly. Conversely it would appear from our results that the introduction of anticholinergic drugs in patients treated initially with levodopa is likely to produce additional benefit, particularly when the maximum tolerated dose of levodopa is small.     

Behavioural and neurochemical evaluation of Perment an herbal formulation in chronic unpredictable mild stress induced depressive model

Perment, a polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The aim of the present study was to explore the behavioural effects and to understand possible mode of action of Perment in stress induced depressive model. Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour. Using standard protocols plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant action than anxiolytic activity. Further Perment increased the plasma noradrenaline and serotonin levels in stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with Perment treatment. However the adrenal corticosterone level is decreased with Perment. It can be concluded that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic activity, which may be mediated through adrenergic and serotonergic system activation. Currently the formulation is clinically used as anxiolytic but the present results suggest that the formulation can also be indicated in patients affected with depression.     

Is mood chemistry?

The chemical hypothesis of depression suggests that mood disorders are caused by a chemical imbalance in the brain, which can be corrected by antidepressant drugs. However, recent evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression, and that antidepressant drugs induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood.     

Chronic Fenfluramine Administration: Some Cerebral Effects

Human cerebral function was monitored electrophysiologically during sleep over a period of months before, during, and after the intake of fenfluramine, 40-120 mg/day. Effects included dose-related reduction of paradoxical sleep, increase of intra-sleep restlessness, and changes in E.E.G. slow-wave sleep. It is hypothesized that weight loss may be associated with increase of the last. Grinding of teeth (bruxism) also was noted.Long-term studies make it possible to demonstrate changing central effects with time, including tolerance phenomena. Withdrawal abnormalities are related to the time taken for the drug to be eliminated—in the present case reaching a maximum four days after withdrawal.     

Effect of Fenfluramine on Human Growth Hormone Release

In order to investigate the effect of fenfluramine on hormonal and metabolic changes with exercise, five normal volunteers have been studied during and after 20 minutes of steady exercise on a bicycle ergometer after injection of fenfluramine (20 mg intravenously). Fenfluramine abolished the rise of plasma human growth hormone (HGH) which occurred in control investigations. Fenfluramine also affected plasma insulin, blood glucose, and ketone body levels.The acute effect of fenfluramine on the release of growth hormone was examined further by studying its effect in patients with acromegaly. A marked depression of growth hormone occurred both at rest and with exercise. These observations indicate that fenfluramine has a direct effect on pathways controlling growth hormone release. We also suggest that this action may have practical use in the medical treatment of acromegaly.     

The Dynamics of Mood and Coping in Bipolar Disorder: Longitudinal Investigations of the Inter-Relationship between Affect,Self-Esteem and Response Styles

Background

Previous research has suggested that the way bipolar patients respond to depressive mood impacts on the future course of the illness, with rumination prolonging depression and risk-taking possibly triggering hypomania. However, the relationship over time between variables such as mood, self-esteem, and response style to negative affect is complex and has not been directly examined in any previous study – an important limitation, which the present study seeks to address.

Methods

In order to maximize ecological validity, individuals diagnosed with bipolar disorder (N = 48) reported mood, self-esteem and response styles to depression, together with contextual information, up to 60 times over a period of six days, using experience sampling diaries. Entries were cued by quasi-random bleeps from digital watches. Longitudinal multilevel models were estimated, with mood and self-esteem as predictors of subsequent response styles. Similar models were then estimated with response styles as predictors of subsequent mood and self-esteem. Cross-sectional associations of daily-life correlates with symptoms were also examined.

Results

Cross-sectionally, symptoms of depression as well as mania were significantly related to low mood and self-esteem, and their increased fluctuations. Longitudinally, low mood significantly predicted rumination, and engaging in rumination dampened mood at the subsequent time point. Furthermore, high positive mood (marginally) instigated high risk-taking, and in turn engaging in risk-taking resulted in increased positive mood. Adaptive coping (i.e. problem-solving and distraction) was found to be an effective coping style in improving mood and self-esteem.

Conclusions

This study is the first to directly test the relevance of response style theory, originally developed to explain unipolar depression, to understand symptom changes in bipolar disorder patients. The findings show that response styles significantly impact on subsequent mood but some of these effects are modulated by current mood state. Theoretical and clinical implications are discussed.     

Addiction and the brain: the neurobiology of compulsion and its persistence

People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue. Addiction is characterized by a long-lasting risk of relapse, which is often initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory.     

Enhancement of the 5-HT neurotransmission by antidepressant treatments

The hypothesis of an etiopathogenic role of 5-HT and that of a mediation by the 5-HT system in the effect of antidepressant treatments have often been confused. Little unequivocal evidence exists for a 5-HT deficit in depression. However, several recent animal and clinical data suggest that the 5-HT system might contribute to the therapeutic effect of various antidepressant treatments. Long-term administration of tricyclic antidepressant (TCA) drugs induces a sensitization of rat forebrain neurons to iontophoretically-applied 5-HT. Repeated electroconvulsive shocks result also in an increased sensitivity of forebrain 5-HT receptors. However, chronic administration of a new antidepressant drug, zimelidine, a potent and long-lasting 5-HT uptake blocker, fails to modify 5-HT receptor sensitivity. These results suggest that enhancement of 5-HT neurotransmission obtained via either pre- or postsynaptic mechanisms might determine the antidepressant effect of these treatments. In a recent clinical study, we observed that lithium administration to TCA-resistant depressive patients induced a rapid relief of depression. It is possible that the presynaptic enhancing effect of lithium on the 5-HT system might unveil the TCA-induced sensitization of the postsynaptic 5-HT receptors. Most depressed patients exhibit marked diurnal variations of mood. Preliminary experiments in rats revealed that the responsiveness of hippocampal neurons to iontophoretically-applied 5-HT is enhanced in the evening. Similar diurnal variations of 5-HT receptor sensitivity might occur in human brain and be related to diurnal variation of mood in depression. Since normal individuals do not show these fluctuations of mood, it is proposed that the "mood regulating system" might become 5-HT dependent in depressed patients.     

A comparison of rh-TSH and thyroid hormone withdrawal in patients with differentiated thyroid cancer: preliminary evidence for an influence of age on the subjective well-being in hypothyroidism

We aimed to investigate the subjective well-being in patients with differentiated thyroid cancer after hormone withdrawal. Since this might be confounded by psycho-oncological processes unrelated to hypothyroidism we intended to minimize such factors by only including patients with a history of uneventful follow-up examinations for several years. We investigated 67 patients applying the General Health Questionnaire (GHQ-12) at 3 time points t1, t2, and t3. The time point t2 represented an intensified follow-up examination 5 years after thyroidectomy, which was performed either on hormone withdrawal (49 patients) or using rh-TSH (18 patients). The time points t1 and t3 took place during follow-up examinations 6 months before and after t2 in a euthyroid state. Additionally, we assessed the impact of age, gender, family status, and education on the GHQ-12 score at all 3 time points. Within the hormone withdrawal group the analyses demonstrated a significant difference between t1 and t2 as well as t3 and t2. Additionally, there was a significant negative correlation of age with GHQ-12 sum scores at t2, but not at t1 or t3. Subgroup analyses at t2 indicated that the subjective well-being in younger patients was more impaired compared to elderly patients. The between-group analysis showed no significant differences. However, concerning the age effect there was a significant difference between the subgroup of young hypothyroid patients and the total rh-TSH group at t2. We demonstrated preliminary evidence for an influence of age on the subjective well-being in hypothyroidism suggesting that younger subjects are subjectively more impaired by hypothyroidism than elderly ones.     

La dépression et le traitement antidépresseur: de la neurotoxicité à la neurogenèse

Major depressive disorder is characterized by structural and neurochemical changes in limbic structures, including the hippocampus that regulates mood and cognitive functions. Hippocampal atrophy is observed in patients with depression: structural changes in the hippocampus associated with depression include dendritic atrophy, decreased adult neurogenesis and reduced volume. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, episodic verbal memory and emotions are altered in depression. Chronic stress exposure and depression leads to hippocampal atrophy and cell loss as well as to decreased expression of neurotrophic growth factors. All types of antidepressant drugs reverse or block the effects of stress. Chronic antidepressant administration upregulates neurogenesis and neuroplasticity in the adult hippocampus and these cellular responses are required for the effects of antidepressants in animal models of depression.     

Long-term effects of nicotine on the forced swimming test in mice: an experimental model for the study of depression caused by smoke

Large evidence showing an association between depression and tobacco smoking is known. Nicotine is the active chemical responsible for smoking addiction, and its withdrawal may induce in smokers greater sensitivity to stress. Our aim has been to investigate the links between tobacco addiction and depression by studying the long-term effects of repeated administration of nicotine followed by dependence, to forced swimming test, serotonin content and 5-HT(1A) expression in diencephalon. Dependence has been induced by daily subcutaneous injection in mice of nicotine (2mg/kg four injections daily) for 15 days and assessed after nicotine withdrawal with an abstinence scale; control animals received daily subcutaneous injection of saline for the same period. Experiments on forced swimming test have been carried out at t=0 (last day of nicotine or saline treatment), and 15, 30, 45 and 60 days after saline or nicotine withdrawal. Both control mice and nicotine mice have been pre-treated with oral 5-hydroxy-tryptophan (12.5-50mg/kg), precursor of serotonin, before forced swimming test. Nicotine mice have shown on forced swimming test a significant increase of immobility time compared to control mice. This increase was not evident in nicotine mice treated with 5-hydroxy-tryptophan and treatment with the selective serotonin receptorial antagonist WAY 100635 (WAY) abolished 5-hydroxy-tryptophan effects. Evaluation of diencephalic serotonin, performed at t=0 showed an increase of diencephalic serotonin content, while serotonin measured 15, 30, 45 and 60 days after nicotine withdrawal, was significantly reduced in nicotine mice compared to control mice. Western blot analysis showed a great reduction of 5-HT(1A) receptor expression in nicotine mice measured at t=0 (last day of treatment) and at 15 and 30 days after nicotine withdrawal compared to control mice. Our results show that (i) behavioural alterations estimated with forced swimming test and (ii) changes in diencephalic serotonin content and 5-HT(1A) receptor expression, are present since nicotine is withdrawn even after a long time, suggesting a role of serotonin in mood disorders eventually occurring following smoking cessation.     

Plasma prolactin changes following fenfluramine in depressed patients compared to controls: An evaluation of central serotonergic responsibility in depression

In an attempt to evaluate the responsiveness of the serotonergic neurotransmitter system in depression, fenfluramine, a serotonin releasing agent, was administered to 18 depressed patients and 10 controls, and placebo was administered to 16 of the depressed patients in a double-blind paradigm. Plasma prolactin levels were measured prior to and for five hours following fenfluramine. Fenfluramine produced a significant increase in prolactin in both patients and controls. However, the prolactin response to fenfluramine whether measured as an absolute increase or percent increase from baseline was significantly less in depressed patients than controls. This difference remained equally statistically significant when age-and-sex-matched pairs of depressed patients and controls were compared. These results suggest that the central serotonergic system is less responsive in depressed patients than controls.     

Maternity blues and major endocrine changes: Cardiff puerperal mood and hormone study II.

OBJECTIVES--To define relation between mood and concentrations of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. DESIGN--Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. SETTING--Antenatal clinic in university hospital, obstetric inpatient unit, patients'' homes. SUBJECTS--120 of 156 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because caesarean section required. MAIN OUTCOME MEASURES--Concentrations of progesterone and cortisol in saliva samples; women''s moods assessed by various scores for depression. RESULTS--Changes in salivary progesterone and cortisol concentrations were similar to those already characterised for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day five postpartum (P < 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P < 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P > or = 0.01), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score > or = 8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmol/l v 3210 pmol/l respectively, P = 0.03; ten days postpartum 88 pmol/l v 114 pmol/l, P = 0.048). Cortisol concentrations were not significantly associated with mood. CONCLUSION--Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.     

The Associations between Self-Consciousness,Depressive State and Craving to Drink among Alcohol Dependent Patients Undergoing Protracted Withdrawal

Context

In order to understand how certain personality traits influence the relation between depression symptoms and craving for alcohol, trait self-consciousness (trait SC) was examined during a withdrawal and detoxification program.

Methods

Craving (Obsessive and Compulsive Drinking Scale), depressive state (Beck Depression Inventory) and trait SC (Revised Self-Consciousness Scale) were assessed in alcohol-dependent inpatients (DSM-IV, N = 30) both at the beginning (T1: day 1 or 2) and at the end (T2: day 14 to18) of protracted withdrawal during rehabilitation.

Results

A significant decrease in craving and depressive symptoms was observed from T1 to T2, while SC scores remained stable. At both times, strong positive correlations were observed between craving and depression. Moreover, regression analyses indicated that trait SC significantly moderated the impact of depression on cravings for alcohol.

Limitations

This study was performed on a relatively small sample size. Administration of medications during detoxification treatment can also be a confounding factor. Finally, craving could have been evaluated through other types of measurements.

Conclusions

During protracted withdrawal, alcohol craving decreased with the same magnitude as depressive mood. Depressive symptoms were related to alcohol craving but only among patients with high trait SC scores. Our results suggest that metacognitive approaches targeting SC could decrease craving and, in turn, prevent future relapses.     

Gastrointestinal Disturbances Associated with Withdrawal of Ataractic Drugs

The psychological effects of abrupt withdrawal of ataractic drugs have been studied by others. Physical symptoms also occur under such circumstances and include abdominal pain, nausea and vomiting. Forty patients were divided into four groups of 10, each group receiving one of the following drugs: chlorpromazine, thioridazine, perphenazine or chlorprothixene. This medication was then suddenly withdrawn. In each of the chlorpromazine and thioridazine groups, three patients had gastrointestinal symptoms within 48 hours, lasting one to eight days. One patient on chlorprothixene, 450 mg. daily, experienced symptoms for six days. Perphenazine withdrawal produced no such symptoms. Thioridazine has little antiemetic action but perphenazine is prescribed for vomiting; hence it seems unlikely that the reported symptoms are due to a rebound action on the vomiting centre.These findings are relevant to the situation of withdrawal of ataractics prior to administration of anesthetics and to drug studies involving cross-over from an active compound to a placebo. The increasing use of ataractics suggests that this additional diagnostic possibility should be considered in the presence of obscure gastrointestinal symptoms.     

Different affective response to opioid withdrawal in adolescent and adult mice

AimsDrug withdrawal is suggested to play a role in precipitating mood disorders in individuals with familial predisposition. Age-related differences in affective responses to withdrawal might explain the increased risk of mental illnesses when drug use begins during adolescence. Since there is a lack of animal research examining the effects of opioid withdrawal during adolescence, the present study examined whether there are age-related differences in affective responses to opioid withdrawal.Main methodsAdolescent and adult mice were injected with two different morphine regimens, namely low and high, which differed in the dosage. Three and nine days following discontinuation of morphine administration, immobility time in the forced swim test (FST) and locomotion (total distance traveled) were evaluated.Key findingsOn withdrawal day 3 (WD3), adolescent mice exhibited a decrease in immobility as compared to controls. No significant differences in immobility were observed on withdrawal day 9 (WD9). This effect on FST behaviors was not due to changes in overall motor activity, since no differences in locomotion were observed on either WD3 or WD9 in adolescent mice. In adults, no differences in either FST or locomotor behaviors were observed on WD3. As expected, on WD9, adult mice exhibited an increase in immobility and a decrease in locomotion.SignificanceThis study demonstrates age-dependent differences in both FST scores and locomotor behaviors during opioid withdrawal. FST behaviors are classically used to evaluate mood in rodents, thus this study suggests that opioid withdrawal might affect mood differentially across age.     

Rotational responses to serotonergic and dopaminergic agonists after unilateral dihydroxytryptamine lesions of the medial forebrain bundle: co-operative interactions of serotonin and dopamine in neostriatum.

Rats with unilateral 5,7-DHT lesions, but not 5,6-DHT lesions, showed rotational responses to 5-HTergic drugs (5MeODMT and fenfluramine) that were qualitatively similar to those induced by DAergic drugs (apomorphine and amphetamine) after 6-OHDA lesions. However, 5,7-DHT-lesioned rats also themselves showed rotational responses to DAergic drugs. The merits and limitations of a unilateral 5,7-DHT-lesioned rotating rat model for studying 5-HTergic function are discussed. It is suggested that 5-HT and DA may function in a co-operative manner in the striatum. These findings may be important for the rational pharmacotherapy of Parkinson's disease in which 5-HT as well as DA has been shown to be substantially depleted.     

Effects of fenfluramine and ritanserin on prolactin response to insulin-induced hypoglycemia in obese patients: evidence for failure of the serotoninergic system

In order to study the hypothesized impairment of the serotoninergic system in human obesity, an insulin tolerance test (ITT) was carried out on 12 obese normoprolactinemic women and on 6 normal-weight women before (A) and after (B) the administration of a serotoninergic drug, fenfluramine (60 mg twice a day per os for 7 days). After a washout period, a new ITT (C) followed the administration of fenfluramine at the same dose, associated with a specific S2 blocker receptor agent, ritanserin (30 mg/day for the first 2 days and 20 mg/day for a further 5 days). In obese subjects, the prolactin (PRL) response to ITT A was reduced as compared to the controls: in 6 patients ('nonresponders') the PRL levels did not change, while in the other 6 ('responders') they increased (p less than 0.003) but less than in the controls (p less than 0.02). In normal-weight subjects, the administration of fenfluramine alone or with ritanserin did not modify the PRL response to ITT. In the responders, the serotoninergic drug normalized the PRL response to ITT while significantly improving it in the nonresponders; these effects were not antagonized by ritanserin. In conclusion, our data suggest that the serotoninergic system of obese patients is impaired and that the different secretory pattern observed in the two groups before and after fenfluramine may reflect differing degrees of this impairment.