Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects.

The chiral antidepressant venlafaxine (VEN) is both a serotonin and a norepinephrine uptake inhibitor. CYP2D6 and CYP3A4 contribute to its metabolism, which has been shown to be stereoselective. Ten CYP2D6 genotyped and depressive (F32x and F33x, ICD-10) patients participated in an open study on the pharmacokinetic and pharmacodynamic consequences of a carbamazepine augmentation in VEN non-responders. After an initial 4-week treatment with VEN (195 +/- 52 mg/day), the only poor metabolizer out of 10 depressive patients had the highest plasma concentrations of S-VEN and R-VEN, respectively, whereas those of R-O-demethyl-VEN were lowest. Five non-responders completed the second 4-week study period, during which they were submitted to a combined VEN-carbamazepine treatment. In the only non-responder to this combined treatment, there was a dramatic decrease of both enantiomers of VEN, O-demethylvenlafaxine, N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine in plasma, which suggests non-compliance, although metabolic induction by carbamazepine cannot entirely be excluded. The administration of carbamazepine [mean +/- SD, range: 360 +/- 89 (200-400) mg/day] over 4 weeks did not result in a significant modification of the plasma concentrations of the enantiomers of VEN and its O- and N-demethylated metabolites in the other patients. In conclusion, these preliminary observations suggest that the combination of VEN and carbamazepine represents an interesting augmentation strategy by its efficacy, tolerance and absence of pharmacokinetic modifications. However, these findings should be verified in a more comprehensive study.

Dreaming without REM sleep.

To test whether mental activities collected from non-REM sleep are influenced by REM sleep, we suppressed REM sleep using clomipramine 50mg (an antidepressant) or placebo in the evening, in a double blind cross-over design, in 11 healthy young men. Subjects were awakened every hour and asked about their mental activity. The marked (81%, range 39-98%) REM-sleep suppression induced by clomipramine did not substantially affect any aspects of dream recall (report length, complexity, bizarreness, pleasantness and self-perception of dream or thought-like mentation). Since long, complex and bizarre dreams persist even after suppressing REM sleep either partially or totally, it suggests that the generation of mental activity during sleep is independent of sleep stage.

Very long half-life of paroxetine following intoxication in an extensive cytochrome P4502D6 metabolizer

A very long half-life of paroxetine (195 h instead of the usual value of around 16 h) was measured after an overdose with 2 g paroxetine and 1 g clorazepate in a patient who was an extensive cytochrome P4502D6 metabolizer. The patient recovered well without any clinically significant complications. A consequence of the close monitoring of paroxetine levels in this patient was that it was decided not to reintroduce any other antidepressant despite her suicide attempt, until normal levels of paroxetine had been reached, which took over 1 month.

How to keep the brain awake? : pharmacogenomics and aging effects on sleep-wake regulation in inbred mice

ABSTRACT : Genetic approach in the sleep field is at the beginning of its wide expansion. Transitions between sleep and wakefulness, and the maintenance of these states are driven by complex neurobiologic mechanisms with reciprocal interactions. Impairment in both transitions and maintenance of behavioral states leads to debilitating conditions. The major symptom being excessive daytime sleepiness, characterizing most sleep disorders but also a wide variety of psychiatric and neurologic disorders, as well as the elderly. Until now, most wake-promoting drugs available directly (e.g., amphetamines and possibly modafinil) or indirectly (e.g., caffeine) provokes dopamine release which is believed to influence the abuse potential of these drugs. The effects of genetic components were assessed here, on drug-induced wakefulness and age-related sleep changes in three inbred mouse strains [AKR/J, C57BL/6J, DBA/2J] that differ in their major sleep phenotypes. Three wake-promoting drugs were used; d-amphetamine, a classical stimulant, modafinil, the most widely-prescribed stimulant, and YKP-10A, a novel wake-promoting agent with antidepressant proprieties. Electrical activity (Electroencephalogram) and gene expression of the brain were assessed and indicate a highly genotype-dependant response to wake promotion and subsequent recovery sleep. Aging effects on sleep-wake regulation were also strongly influenced by genetic determinants. By assessing the age-dependant effects at several time points (from 3 months to 2 years old mice), we found a strong genetic effect on vigilance states. These studies demonstrate a critical role for genetic factors neglected till now in the fields of pharmacology and aging effects on vigilance states.

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Deletion of CREB-Regulated Transcription Coactivator 1 Induces Pathological Aggression, Depression-Related Behaviors, and Neuroplasticity Genes Dysregulation in Mice.

BACKGROUND: Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription coactivator 1 (CRTC1). METHODS: To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. RESULTS: We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1(-/-) mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation, together with increased behavioral despair, anhedonia, and anxiety-related behavior in the novelty-induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1(-/-) mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty-induced hypophagia test. Crtc1(-/-) mice strikingly show, in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex, a concomitant decreased expression of several susceptibility genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes. CONCLUSIONS: Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors.

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

Pharmacological treatment of behavioral and psychological symptoms of dementia (BPSD) in nursing homes: development of practice recommendations in a Swiss canton

OBJECTIVES: In 2002, the canton of Fribourg, Switzerland, implemented a coordinated pharmaceutical care service in nursing homes to promote rational drug use. In the context of this service, a project was conducted to develop recommendations for the pharmacological management of behavioral and psychological symptoms of dementia (BPSD) in nursing home residents. DESIGN AND METHODS: Selected evidence-based guidelines and meta-analysis sources related to the management of depression, insomnia, and agitation in dementia patients were systematically searched and evaluated. Evidence and controversies regarding the pharmacological treatment of the most common BPSD symptoms were reviewed, and treatment algorithms were developed. RESULTS: Ten evidence-based guidelines and meta-analyses for BPSD management were identified, with none specifically addressing issues related to nursing home residents. Based on this literature, recommendations were developed for the practice of pharmacological management of depression, sleep disturbances, and agitation in nursing home residents. For depression, SSRIs are considered the first choice if an antidepressant is required. No clear evidence has been found for sleep disturbances; the underlying conditions need to be investigated closely before the introduction of any drug therapy. Many drugs have been investigated for the treatment of agitation, and if necessary, antipsychotics could be used, although they have significant side effects. Several areas of uncertainty were identified, such as the current controversy about typical and atypical antipsychotic use or the appropriateness of cholinesterase inhibitors for controlling agitation. Treatment algorithms were presented to general practitioners, pharmacists, and medical directors of nursing homes in the canton of Fribourg, and will now be implemented progressively, using educational sessions, pharmaceutical counseling, and monitoring. CONCLUSION: Based on existing evidence-based studies, recommendations were developed for the practice of pharmacological management of depression, sleep disturbances, and agitation in nursing home residents. It should be further studied whether these algorithms implemented through pharmaceutical care services will improve psychotropic drug prescriptions and prevent drug-related problems in nursing home residents

Death following acute poisoning by moclobemide

A fatality due to ingestion of a reversible inhibitor of monoamine-oxidase A (MAO-A) is reported. Moclobemide is generally considered as a safe drug far less toxic than tricyclic anti-depressants. However, severe intoxications may result from interactions with other drugs and food such as selective serotonin reuptake inhibitors (SSRIs), anti-Parkinsonians of the MAOI-type (e.g. selegiline) or tyramine from ripe cheese or other sources. In the present case, high levels of moclobemide were measured in peripheral blood exceeding toxic values reported so far in the scientific literature. The body fluid concentrations of moclobemide were of 498 mg/l in peripheral whole blood, 96.3 mg/l in urine while an amount of approximately 33 g could be recovered from gastric contents. The other xenobiotics were considered of little toxicological relevance. The victim (male, 48-year-old) had a past history of depression and committed one suicide attempt 2 years before death. Autopsy revealed no evidence of significant natural disease or injury. It was concluded that the manner of death was suicide and that the unique cause of death was massive ingestion of moclobemide.

Regulation of neurotrophic factors and energy metabolism by antidepressants in astrocytes.

There is growing evidence that astrocytes are involved in the neuropathology of major depression. In particular, decreases in glial cell density observed in the cerebral cortex of individuals with major depressive disorder are accompanied by a reduction of several astrocytic markers suggesting that astrocyte dysfunction may contribute to the pathophysiology of major depression. In rodents, glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors and antidepressant treatment prevents the stress-induced reduction of astrocyte number in the hippocampus. Collectively, these data support the existence of a link between astrocyte loss or dysfunction, depressive-like behavior and antidepressant treatment. Astrocytes are increasingly recognized to play important roles in neuronal development, neurotransmission, synaptic plasticity and maintenance of brain homeostasis. It is also well established that astrocytes provide trophic, structural, and metabolic support to neurons. In this article, we review evidence that antidepressants regulate energy metabolism and neurotrophic factor expression with particular emphasis on studies in astrocytes. These observations support a role for astrocytes as new targets for antidepressants. The contribution of changes in astrocyte glucose metabolism and neurotrophic factor expression to the therapeutic effects of antidepressants remains to be established.

FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: Basal contents and effects of psychotropic treatments.

Enhanced brain apoptosis (neurons and glia) may be involved in major depression (MD) and schizophrenia (SZ), mainly through the activation of the intrinsic (mitochondrial) apoptotic pathway. In the extrinsic death pathway, pro-apoptotic Fas-associated death domain (FADD) adaptor and its non-apoptotic p-Ser194 FADD form have critical roles interacting with other death regulators such as phosphoprotein enriched in astrocytes of 15kDa (PEA-15) and extracellular signal-regulated kinase (ERK). The basal status of FADD (protein and messenger RNA (mRNA)) and the effects of psychotropic drugs (detected in blood/urine samples) were first assessed in postmortem prefrontal cortex of MD and SZ subjects (including a non-MD/SZ suicide group). In MD, p-FADD, but not total FADD (and mRNA), was increased (26%, n=24; all MD subjects) as well as p-FADD/FADD ratio (a pro-survival marker) in antidepressant-free MD subjects (50%, n=10). In contrast, cortical FADD (and mRNA), p-FADD, and p-FADD/FADD were not altered in SZ brains (n=21) regardless of antipsychotic medications (except enhanced mRNA in treated subjects). Similar negative results were quantified in the non-MD/SZ suicide group. In MD, the regulation of multifunctional PEA-15 (i.e., p-Ser116 PEA-15 blocks pro-apoptotic FADD and PEA-15 prevents pro-survival ERK action) and the modulation of p-ERK1/2 were also investigated. Cortical p-PEA-15 was not changed whereas PEA-15 was increased mainly in antidepressant-treated subjects (16-20%). Interestingly, cortical p-ERK1/2/ERK1/2 ratio was reduced (33%) in antidepressant-free when compared to antidepressant-treated MD subjects. The neurochemical adaptations of brain FADD (increased p-FADD and pro-survival p-FADD/FADD ratio), as well as its interaction with PEA-15, could play a major role to counteract the known activation of the mitochondrial apoptotic pathway in MD.

Determination of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in the plasma and urine of mianserin-treated patients.

An HPLC method is presented which allows the measurement in the same run of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in plasma and urine of mianserin-treated patients. Limits of quantitation for the (S)- and (R)-enantiomers of mianserin and desmethylmianserin were 4 and 2.5 ng/ml, respectively, in plasma, and for the (S)- and (R)-enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin 5, 2.5, and 5 ng/ml, respectively, in urine. The measured ratios of (S)-mianserin/(R)-mianserin and (S)-desmethylmianserin/(R)-desmethylmianserin in the plasmas of 10 mianserin-treated patients, all extensive metabolizers of debrisoquine as determined by CYP2D6 genotyping, varied, respectively, from 1.0 to 4.06 and from 0.19 to 0.64. As the enantiomers of mianserin differ in their pharmacological profile, these results could partially explain why, until now, no consistent relationship has been established between the therapeutic response and total [(S) + (R)] plasma levels of this antidepressant.

Chronic pain and antidepressants: A systematic review of efficacy

Background and aims: chronic pain is a major public health care problem with a prevalence in Europe as high as 19% in the general population (Breivik et al. 2006). Beside classical analgesics, Antidepressants (AD) remain an essential part of the therapeutic armamentarium. The present study was aimed at reviewing current evidence for efficacy of AD in main chronic pain conditions. Methods: We performed a systematic literature search through Ovid Medline, Psychinfo and Cochrane database to retrieve controlled studies and reviews on the use of AD in specific chronic pain conditions: neuropathic pain, migraine and tension-type headache, muskuloskeletal pain, and fibromyalgia. Results: There is sufficient data to support the use of tricyclic antidepressants (TCAs) in neuropathic pain, migraine and tension-type headache. There is also good evidence for a beneficial effect of TCAs in chronic low back pain and fibromyalgia. The SNRI venlafaxine and duloxetine are drugs with less established efficacy in neuropathic pain, tension type headache and fibromyalgia, but may be recommended as second line treatment. Available data do not support the use of SSRIs in any of these conditions. Given the limitations of available studies, there is still room to better characterize putative benefits of SNRIs and SSRIs in some of these conditions. Conclusions: Efficacy of AD in chronic pain appear to vary greatly between type of AD. Beneficial effects when present seem independent of the effect on mood. There is a lack of long term controlled trials in most type of chronic pain conditions.

Treating tobacco use and dependence in clinical practice.

Physicians are in a unique position to advise smokers to quit by the ability to integrate the various aspects of nicotine dependence. This review provides an overview of the intervention strategies for smokers presented in a primary care setting. The strategies that are used for smoking cessation counselling differ according to the patient's readiness to quit. For smokers who do not intend to give up smoking, physicians should inform about tobacco use and the benefits of cessation. For smokers who are dissonant, physicians should use motivational strategies, such as discussing the barriers to successful cessation and their solutions. For smokers who are ready to quit, the physician should show strong support, help set a date to quit, prescribe pharmaceutical therapies for nicotine dependence, such as nicotine replacement therapy (i.e., gum, transdermal patch, nasal spray, mouth inhaler, lozenges, and micro and sublingual tablets) and/or bupropion (an atypical antidepressant thought to work by blocking the neural re-uptake of dopamine and/or noradrenaline), with instructions for use, and suggest behavioural strategies to prevent relapse. The efficacy of all of these pharmacotherapies is comparable, roughly doubling the cessation rates over control conditions.