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Commentary on Domschke, et al., Magnetoencephalographic correlates of emotionalprocessing in major depression before and after pharmacological treatment. Understanding the therapeutic effects of psychotropic medication has typically been approached, reasonably enough, with an analysis of the effects on brain chemistry. For example, the effective antidepressant mirtazapine is thought to affect both norepinephrine and serotonin neuromodulators, both of which are important to mood disorders such as major depression. However, understanding the full neuropsychopharmacology of a therapeutic agent requires an analysis of the multiple levels of neural self-regulation that are involved in the disorder and that are affected by the drug. It has long been apparent that if the mechanism of drug action were simply a correction of a biochemical imbalance, then the therapeutic effect would be rapid, limited only by the pharmacokinetics (Cooper et al., 2002). Instead, antidepressants typically require weeks of continued administration before they achieve a therapeutic effect. Although the complexity of drug action is familiar to most psychopathology researchers, clinicians are typically provided with only a superficial training on the neurophysiological and neuropsychological mechanisms for both psychopathology itself and the therapeutic effects of drugs. The result of this limited training is that a patient with depression, for example, is often told by the physician they have a “biochemical imbalance” that will be corrected by drug therapy. Not only is this explanation scientifically incorrect, …

We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects. All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine.

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these two exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(βNon-exposed = 0.06, βSRI-exposed = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status—both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)—was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 methylation status, which, in turn, appeared to be associated with birth weight.

Most drugs are prescribed for several illnesses, but it took several years for psychotropic drugs to have multiple clinical indications. Our search for serotonergic drugs in affective illnesses and related disorders led to new off-label indications for fluoxetine, sertraline, tryptophan, clonazepam, alprazolam, tomoxetine, buproprion, duloxetine, risperidone and gabapentin. Various clinical trial designs were used for these proof-of-concept studies. Novel therapeutic uses of benzodiazepines, such as in panic disorder and mania, were found with the introduction of 2 high-potency benzodiazepines, clonazepam and alprazolam, which were thought to have serotonergic properties. Our initial clinical trials of fluoxetine and sertraline led to their approved indications in the treatment of obsessive–compulsive disorder, and our trials of gabapentin led to new indications in anxiety disorders (generalized anxiety, panic attack and social phobia) and sleep disorders (insomnia).

A series of three para-benzoquinone mono-oximes and four oxy-derivatives were prepared and tested for their antidepressant properties. The (4E) oxime of 2-isopropyl-5- methyl-para-benzoquinone (4) and the corresponding 2-diethylamino-ethyl derivative (10) present antidepressant activities and were slightly more potent than the reference standard.

Background: Moclobemide, a benzamide, is one of the new-generation monoamine oxidase-A inhibitors (MAO-AIs) which belongs to the class of reversible inhibitors of monoamine oxidase (RIMA). Numerous studies have shown that moclobemide is well-tolerated and as effective as other antidepressants. So far, there is no evidence available regarding its efficacy and tolerability in India. Aim: To compare the efficacy and safety of moclobemide with that of imipramine, a tricyclic antidepressant, in the treatment of major depressive disorder. Methods: In this prospective study, patients (n=60) were randomly assigned to treatment with moclobemide or imipramine for 6 weeks. Efficacy of the drugs was assessed by observing the mean change in scores on the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Scale (MADRS). Results: Both the groups showed significant decrease in scores at the end of 6 weeks. Patients who received moclobemide had a better side-effect profile. Conclusion: Moclobemide is an effective antidepressant and is better tolerated than imipramine.

Personalized medicine - the adaptation of therapies based on an individual's genetic and molecular profile - is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

Despite NICE guidance that should have limited it, antidepressant prescribing continues to increase. Research evidence suggests that much if not all of the observed efficacy should be attributed to complex non-specific effects rather than ‘restoration of disturbed brain chemistry’. According to this view the uncertain benefits of antidepressants are unlikely to outweigh the risks, suggesting the need to explore other approaches to treatment.

Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. Methods: We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. Results: We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. Limitations: We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. Conclusion: Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development.

Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults.This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (-3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction.Limitations to our study included short treatment duration and lack of an active control arm.Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population.NCT01377194.

Introduction: Inflammatory pain is a common sign of chronic diseases. Some brain regions such as locus coeruleus (LC) of the brainstem nor-epinephrine (NE) system have a key role in The mechanisms of the pain modulation and dependence. Bupropion synthesized as an antidepressant, but it is using for smoke cessation. It can change morphine withdrawal signs such as pain related behaviors. This study tested the acute effect of intra-LC microinfusion of bupropion on the formalin-induced pain behavior in rats. Methods: Wistar male rats were divided into 6 groups (control-naïve, control-operated, shamoperated, and 3 treated groups with 10-2, 10-3, 10-4 mol/&mul intra-LC of bupropion). The injection guide cannulae were implanted into LC nuclei bilaterally by stereotaxic coordinated surgery under sterile condition. The sham group received normal saline as drug vehicle but control groups had no intra-LC injections. Formalin (50 &mul, 2.5%) was injected subcutaneously in plantar region of the right hindpaw in all animals (30 min after drug administration in treated animals). Nociceptive signs were observed continuously and registered on-line each minute. Common pain scoring was used for pain assessment. Results: The analysis of data by one-way ANOVA showed that bupropion can reduce pain behavior scores significantly. Bupropion reduced total pain score in the phase 01 (60%) and phase 02 (52%) of maximal behavior compared to the sham group, dose dependently and significantly. The pain scores of controls and sham groups had no significant difference. Discussion: The results showed that bupropion has analgesic effects on LC neurons and can alter the neurochemical involvement of LC in pain process. Bupropion has different and significant effect on early and late phases of formalin test.

International audience; BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT-/-) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT-/- mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).

Objective: To study the prevalence and patterns of sexual dysfunctions in female patients receiving antidepressants. Materials and Methods: Eighty married female patients with a diagnosis of depressive disorder, currently in remission, and receiving a single antidepressant at least for 3 months, were assessed for sexual dysfunction on female sexual function index (FSFI) scale. Results: Thirty four patients (42.5%) receiving antidepressants had FSFI score less than 26.55 and were considered to have sexual dysfunction. When only the domain cutoff scores were used for the whole study sample ( n =80), it was found that 95% had decreased desire, 60% had decreased arousal, 37.5% had decreased lubrication, 63.8 had decreased orgasm, 55% had decreased satisfaction and 25% had pain during sexual activity. Conclusions: To conclude, our study suggests that sexual dysfunction is quite prevalent in married female patients receiving antidepressants and all the domains of sexual functioning are impaired by antidepressants.

1 The clinical pharmacological properties of viloxazine hydrochloride (ICI 58,834, Vivalan), a new antidepressant of novel chemical structure, have been investigated in a series of double-blind randomized studies comparing it with placebo and imipramine. Throughout the studies, viloxazine hydrochloride was given in single doses of 100 mg (expressed as base), and imipramine hydrochloride was given in single doses of 50 mg (expressed as salt). 2 The effect of viloxazine upon the following parameters was measured: pulse rate, blood pressure, forced expiratory volume, reaction time, critical flicker frequency, salivary flow, pupil size and palpebral fissure size. In addition, the possible interaction between viloxazine and alcohol was investigated using measurements of reaction time. 3 Both viloxazine and imipramine produced a transient tachycardia, but no consistent effect on blood pressure was seen. Neither drug had any effect upon forced expiratory volume. 4 The differences that emerged between viloxazine and imipramine were that viloxazine depressed critical flicker frequency whereas imipramine did not, and imipramine prolonged reaction time whilst viloxazine did not. Imipramine reduced salivary flow and increased the size of the pupil and palpebral fissure. Viloxazine did neither. 5 Imipramine was shown to potentiate alcohol whereas, at the doses used, viloxazine did not. 6 It is concluded that viloxazine appears to have less anticholinergic and possibly less sympathomimetic properties than imipramine. It is also concluded that viloxazine, unlike imipramine, does not potentiate alcohol.

Background: Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits, the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown. Methods: The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≧40 years. Participants were randomly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks. An ANCOVA compared improvement in the cognitive composite scores, and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups. Results: There were no differences between the citalopram and placebo groups in changes in cognition. Baseline cognitive status did not moderate antidepressant treatment response. Conclusions: Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention, treatment does not substantially affect the level of cognitive functioning. Given the effects of cognitive deficits associated with schizophrenia on functional disability, there remains an ongoing need to identify effective means of directly ameliorating them.

Difficulties in mother–child interaction are commonly observed in the context of postnatal depression. These difficulties may result in part from the negative cognitive bias present in depression, which may in turn lead to biased negative perceptions of the infant: in particular, these biases encompass the negative appraisal of facial expressions. Given the important role of early mother–child interactions in child development it is vital to investigate potential interventions that might be beneficial in ameliorating the negative cognitive bias. This study aimed to examine the effects of two different antidepressants (reboxetine and citalopram) on the appraisal of infant facial expressions of emotion using a faces rating task, and on attention to infant emotion using an attentional probe. Thirty-nine volunteers were randomly assigned to a double-blind 7-day intervention with either placebo, citalopram or reboxetine. There were significant positive effects on the appraisal of facial expressions; participants assigned to the placebo group rated positive faces less positively than those either in the citalopram or in the reboxetine groups. However, there was no evidence that these drugs had an effect on attentional vigilance. If antidepressants are able to help a mother to perceive her infant’s facial expressions as more positive, this may lead to more positive interactions, thereby potentially mitigating the negative effects of depression on infant development. These findings should be treated with caution until replicated in larger and clinical samples.

12 p., 5 figures, 2 tables and references., Background and purpose: The present study evaluated the role of CB 2 receptors in the regulation of depressive-like behaviours. Transgenic mice overexpressing the CB 2 receptor (CB2xP) were challenged with different types of acute and chronic experimental paradigms to evaluate their response in terms of depressive-like behaviours. Experimental approach: Tail suspension test (TST), novelty-suppressed feeding test (NSFT) and unpredictable chronic mild stress tests (CMS) were carried out in CB2xP mice. Furthermore, acute and chronic antidepressant-like effects of the CB 2 receptor-antagonist AM630 were evaluated by means of the forced swimming test (FST) and CMS, respectively, in wild-type (WT) and CB2xP mice. CB 2 gene expression, brain-derived neurotrophic factor (BDNF) gene and protein expressions were studied in mice exposed to CMS by real-time PCR and immunohistochemistry, respectively. Key results: Overexpression of CB 2 receptors resulted in decreased depressive-like behaviours in the TST and NSFT. CMS failed to alter the TST and sucrose consumption in CB2xP mice. In addition, no changes in BDNF gene and protein expression were observed in stressed CB2xP mice. Interestingly, acute administration of AM630 (1 and 3 mg·kg -1, i.p.) exerted antidepressant-like effects on the FST in WT, but not in CB2xP mice. Chronic administration of AM630 for 4 weeks (1 mg·kg -1; twice daily, i.p.) blocked the effects of CMS on TST, sucrose intake, CB 2 receptor gene, BDNF gene and protein expression in WT mice. Conclusion and implications: Taken together, these results suggest that increased CB 2 receptor expression significantly reduced depressive-related behaviours and that the CB 2 receptor could be a new potential therapeutic target for depressive-related disorders., This research was supported by grants from Ministry of Science and Innovation (SAF 2008-01106) and Ministry of Health (RETICS RD06/0001/1004 and PNSD 2007/061). MSGG is a predoctoral fellow of the Ministry of Science and Innovation. JMPO is a postdoctoral fellow of ‘Fundación para la Investigación y Salud de Castilla La Mancha’ (FISCAM).

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Mirtazapine is an often used antidepressant drug, however insufficient information is available regarding its safety during pregnancy. Therefore, this work was initiated to study the effect of prenatal exposure of mirtazapine on postnatal developments of rats. The study was conducted on pregnant rats to observe the safety profile of mirtazapine in comparison to control. The percentage weight gain, gestation period and litter size of the rats treated with double therapeutic dose (DTD) was significantly lower than the rats treated with therapeutic dose (TD) and rats of control group. However the litter size of the TD treated rats was also found smaller than the control. The offspring were examined through battery of test in order to evaluate their developmental neurotoxicity. The test includes the assessment of postnatal growth, reflex ontogeny, neuromotor abilities, activity level, emotional reactivity and learning ability. The DTD exposure negatively affected on overall growth of pups in comparison to TD exposed pups and control group. Further, the amine concentration in brain was also found significantly lower in DTD exposed pups. Therefore, this study reveals that the treatment of pregnant rats with TD and DTD decreases their litter size. In addition the prenatal exposure of DTD of mirtazapine negatively affects on neurodevelopment of rats.

Aims: The ability to mother her infant is reduced in a woman with postpartum depression (PPD). Although antidepressant treatment effectively improves depressive symptoms, various domains of functioning, for example, work and relationships, do not universally improve with treatment. In this pilot study, we investigated whether maternal role functioning improved with antidepressant treatment in women with PPD. Methods: The pilot study was an exploratory analysis of a larger study. A subset of women (n = 27) from a randomized clinical trial (double-blind, 8-week trial of nortriptyline compared with sertraline) completed three outcome measures of maternal role functioning: gratification in the maternal role, the Infant Care Survey (ICS), and videotapes of maternal-infant interaction. The tapes were analyzed using the Child and Caregiver Mutual Regulation Coding Scale and Noldus Behavioral Coding Software. Results: The two antidepressants were equally efficacious in decreasing depressive symptoms and improving overall functioning and gratification in the maternal role. Differences between times 1 and 2 in the mother-infant interactions were related to time (increasing age of the infant) and not assignment of antidepressant or remission of depression. Conclusions: Effective treatment with two antidepressants improves gratification in the maternal role but not self-efficacy or maternal-infant interaction in women with PPD. Results of the study can help women and their healthcare providers to weigh the benefits of short-term antidepressant treatment in the postpartum period. Future studies should consider outcomes related to a longer duration of treatment.

Depression is one of the leading causes of disability worldwide. The majority of patients suffering from depressive disorder are diagnosed and managed in primary care. Optimal management reduces the risk of relapse and improves the quality of life. The main treatment modalities are antidepressants and psychological therapies. Lifestyle changes, exercise and psychoeducation also play an important role in management.

Five percent of menstruating women have severe premenstrual symptoms and impairment of functioning defined as premenstrual dysphoric disorder (PMDD). Clinically significant premenstrual symptoms occur in at least an additional 20% of menstruating women. The diagnosis of PMDD should be confirmed by prospective symptom charting over 2 menstrual cycles to confirm the timing of the symptoms and to rule out other diagnoses. The burden of illness of PMDD includes disruption of parenting and partner relationships and decreased productivity in work roles. In addition, women with PMDD have increased use of health care services such as clinician visits and increased use of prescription medications and over-the-counter preparations. The etiology of PMDD is multifactorial. In particular, dysregulation of the serotonin and allopregnanolone systems is implicated. Several effective treatment options exist, including serotonergic antidepressant medications and an oral contraceptive that contains ethinyl estradiol and drosperinone. In addition, other hormones that suppress ovulation, anxiolytics, cognitive therapy, chasteberry and calcium may be helpful.

The role of hippocampal atrophy in the pathogenesis of major depression remains under investigation. Here, we show, within a neural network model, that the incorporation of atrophy reproduces the changes observed in cognitive impairment in depression and could also contribute to the maintenance of the depressed mood. Some other clinical observations, such as treatment resistance and frequent relapses of illness, could also be explained within the framework of the model. We also simulate the action of cognitive therapy and a combined treatment of cognitive therapy and antidepressant drugs. Our findings suggest that, in the presence of hippocampal atrophy, the incorporation of antidepressant drugs would be necessary for the reversal of symptomatology.

Flavoprotein monoamine oxidase is located on the outer membrane ofmitochondria. It catalyzes oxidative deamination of monoamine neurotransmitters such asserotonin, norepinephrine and dopamine and hence is a target enzyme for antidepressantdrugs. MAO (mono amine oxidase) has two isoforms, namely MAO-A and MAO-B.MAO-A isoform has higher affinity for serotonin and norepinephrine, while, MAO-Bpreferentially deaminates phenylethylamine and benzylamine. These important propertiesdetermine the clinical importance of MAO inhibitors. Selective MAO-A inhibitors are usedin the treatment of neurological disorders such as depression. In this article we havedeveloped a Hypogen pharmacophore for a set of 64 coumarin analogs and tried to analyzethe intermolecular H-bonds with receptor structure.

Objective To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. Design Nested case-control study. Setting Primary care in the United Kingdom. Participants 146 095 individuals with a first prescription of an antidepressant for depression. Main outcome measures Suicide and non-fatal self harm. Results 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. Conclusion We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.

SummaryIt is suggested that a finding that apparently challenges current practice guidelines, namely that patients with a rapid-cycling pattern of bipolar disorder can take antidepressant monotherapy for months without increasing risk of cycling, may be parsimoniously understood by the way that the investigators defined rapid cycling and by their use of acute-phase fluoxetine monotherapy prior to randomisation to continutaion-phase therapy with fluoxetine, lithium or placebo.

Moclobemide (MB) is an antidepressant drug that selectively and reversibly inhibits monoamine oxidase-A. Recent studies have revealed that antidepressant drugs possess the characters of potent growth-promoting factors for the development of neurogenesis and improve the survival rate of serotonin (5-hydroxytrytamine; 5-HT) neurons. However, whether MB comprises neuroprotection effects or modulates the proliferation of neural stem cells (NSCs) needs to be elucidated.In this study, firstly, we used the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to demonstrate that 50 μM MB can increase the cell viability of NSCs. The result of real-time reverse transcription–polymerase chain reaction (RT–PCR) showed that the induction of MB can upregulate the gene expressions of Bcl-2 and Bcl-xL. By using caspases 8 and 3, ELISA and terminal dUTP nick-end labeling (TUNEL) assay, our data further confirmed that 50 μM MB-treated NSCs can prevent FasL-induced apoptosis.The morphological findings also supported the evidence that MB can facilitate the dendritic development and increase the neurite expansion of NSCs. Moreover, we found that MB treatment increased the expression of Bcl-2 in NSCs through activating the extracellular-regulated kinase (ERK) phosphorylation.By using the triple-staining immunofluorescent study, the percentages of serotonin- and MAP-2-positive cells in the day 7 culture of MB-treated NSCs were significantly increased (P

The irresistible rise of the selective serotonin reuptake inhibitor is a fact of contemporary life; antidepressant prescription volumes and costs have more than trebled since their introduction in the early 1990s.1 There have been other changes too: mental illness can be stigmatising, but with around 30 million prescriptions for antidepressants per year in England and Wales, it could be argued that the medical treatment of depression has been normalised. This phenomenon is not unique to the UK. The view from over here is that the US is the home of widely available and interminable psychotherapy; Americans have seen a similar rise in prescriptions for antidepressants while rates of psychotherapy have remained flat or even …

Background: Double-blind clinical trials comparing citalopram with amitriptyline or other tricyclic antidepressants are lacking in India. Aim: To evaluate the efficacy and safety of the newer antidepressant citalopram in the treatment of major depression. Methods: The clinical acceptability and safety profile of citalopram was assessed and compared with that of amitriptyline in 40 patients in an outpatient set-up. Patients aged 18 to 65 years who fulfilled the diagnostic criteria for a single or recurrent major depressive disorder (as defined by DSM-IV) for a minimum of 2 weeks were enrolled. Patient assessment was done at screening, baseline, end of week 1, week 2, week 3, week 4, week 5 and week 6 for efficacy and safety parameters such as Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) Scale, adverse event follow up, blood pressure and pulse. Three­level statistical analysis including ANOVA was performed on all efficacy measures. Results: On the HDRS the percentage reduction in the mean score for the citalopram group (Group 1) was 72.12%, while that for the amitriptyline group (Group 2) was 67.93%. On the CGI-Improvement Scale, the percentage reduction at the end of the study for the citalopram group was 56.79% while in the amitriptyline group it was 44.70%. Twenty per cent of patients in Group 1 reported adverse events compared to 75% in Group 2. Conclusions: Citalopram is effective in the treatment of major depression at the dosages range of 20-60 mg/ day and its efficacy is equivalent to that of standard tricyclic antidepressants such as amitriptyline, with a substantially better tolerability profile.

Objective: To examine the association between trends in antidepressant prescribing and suicide rates in Australia for 1991-2000. Design: Analysis of databases of suicide and rates of antidepressant prescribing according to age and sex. Setting: Australian Bureau of Statistics data, sales data from the Australian pharmaceutical industry, prescribing data in general practice. Subjects: Men and women aged 15 years and over in 10 year age groups. Main outcome measures: Trends in suicide rates and trends in antidepressant prescribing. Association measured by Spearman9s rank correlations. Results: While overall national rates of suicide did not fall significantly, incidence decreased in older men and women and increased in younger adults. In both men (rs=−0.91; P Conclusions: Changes in suicide rates and exposure to antidepressants in Australia for 1991-2000 are significantly associated. This effect is most apparent in older age groups, in which rates of suicide decreased substantially in association with exposure to antidepressants. The increase in antidepressant prescribing may be a proxy marker for improved overall management of depression. If so, increased prescribing of selective serotonin reuptake inhibitors in general practice may have produced a quantifiable benefit in population mental health. What is already known on this topic There has been a substantial increase in antidepressant prescribing by general practitioners in Australia since the introduction of selective serotoin reuptake inhibitors in the early 1990s Previous studies have indicated an association between increased antidepressant prescribing and reduced suicide rate What this study adds In Australia the rate of suicide fell in older people, the age group most heavily exposed to antidepressants Most antidepressants are now prescribed by general practitioners The association may indicate the improved treatment of depression by general practitioners

Objectives: To determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding. Design: Retrospective cohort study from population based databases. Setting: Ontario, Canada. Participants: 317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended. Main outcome measure: Admission to hospital for acute upper gastrointestinal bleeding. Results: Overall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85). Conclusions: After age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding. What is already known on this topic A case-control study found that the risk of upper gastrointestinal bleeding increases with intake of antidepressants that extensively inhibit serotonin reuptake The study9s validity was questioned because antidepressants were not specifically classified by the extent that they inhibit serotonin reuptake, and absolute differences in bleeding rates between antidepressants were unavailable What this study adds The risk of upper gastrointestinal bleeding in elderly and depressed patients increases with antidepressants having the greatest extent of inhibition of serotonin reuptake This increased risk of bleeding is clinically important for patients with a high risk of bleeding—namely, octogenarians and those with previous upper gastrointestinal bleeding The extent that an antidepressant inhibits serotonin reuptake should be considered when drugs are required for depression in high risk patients