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A novel capillary electrophoresis method was developed for the determination of new 4-aryl-pyrido[1,2-c]pyrimidine derivatives, potential antidepressant agents, in serum. The derivatives have conformationally restricted tryptamine moiety in pharmacophore portion and exhibit high affinity to molecular targets: 5-HT1A receptor and serotonin transporter protein. The separation process was conducted using an eCAP fused-silica capillary, detection wavelength 214 nm, 200 mM phosphate buffer adjusted to pH = 8.0, temperature 20 °C, voltage 5 kV. The proposed method was validated by determining its linearity in the concentration range of 200–1000 ng/mL. A satisfactory linearity was obtained for the method, with R2 from 0.9978 to 0.9999 for all five derivatives and a limit of quantification level from 287.1 to 310.1 ng/mL. The recoveries for all derivatives were in the range from 94.7 to 100%. The speed of obtaining the result of the analysis was only 3 min. The developed method allows to determine all five derivatives both in water solutions and serum. [ABSTRACT FROM AUTHOR]

Forkhead box-O (FoxO) transcriptional factors perform essential functions in several physiological and biological processes. Recent studies have shown that FoxO is implicated in the pathophysiology of depression. Changes in the upstream mediators of FoxOs including brain-derived neurotrophic factor (BDNF) and protein kinase B have been associated with depressive disorder and the antidepressant agents are known to alter the phosphorylation of FoxOs. Moreover, FoxOs might be regulated by serotonin or noradrenaline signaling and the hypothalamic-pituitary-adrenal (HPA)-axis,both of them are associated with the development of the depressive disorder. FoxO also regulates neural morphology, synaptogenesis, and neurogenesis in the hippocampus, which accounts for the pathogenesis of the depressive disorder. The current article underlined the potential functions of FoxOs in the etiology of depressive disorder and formulate few essential proposals for further investigation. The review also proposes that FoxO and its signal pathway might establish possible therapeutic mediators for the management of depressive disorder. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the risk of first-time antidepressant prescriptions as a proxy for depression or anxiety and associated risk factors in patients with prostate cancer and their female partners. Methods: We followed all men (n = 25,126) and their female cohabiting partners (n = 8785) without a history of cancer or antidepressants from the Danish Diet, Cancer and Health cohort from 1997 to 2014 or 2010, respectively. We estimated the cumulative incidence of first-time antidepressant prescriptions in men with prostate cancer compared with cancer-free men and their respective female partners, using the Danish National Prescription Registry. Sociodemographic, lifestyle-related, and clinical risk factors were assessed using Cox regression models. Results: A total of 1828 men were diagnosed with prostate cancer of whom 15% received antidepressants. The unadjusted hazard ratio of antidepressant prescription was 2.18 (95%CI, 1.92, 2.48) for men with prostate cancer and 1.27 (95%CI, 0.87, 1.85) for their partners, compared with cancer-free men and their partners, respectively. After adjusting for sociodemographic, lifestyle-related, and comorbidity factors, this risk was 2-fold to 4-fold increased among patients, but not significantly increased among partners. Significant risk factors among patients were curative and palliative treatment (vs. active surveillance and watchful waiting), nonlocalized disease, and short education. Conclusions: Men with prostate cancer have a higher risk of receiving antidepressant medication than cancer-free men. Clinical characteristics can help clinicians in identifying patients at a high risk of depression or anxiety. Implications for Cancer Survivors: Men with prostate cancer who experience symptoms of depression or anxiety should seek professional help early on. Patient education could aid in raising awareness and reducing the stigma associated with mental disorders. [ABSTRACT FROM AUTHOR]

Background Patients with an antidepressant drug treatment (ADT) report unmet needs and a significant proportion stop their ADT prematurely. Community pharmacists can play a key role in supporting these patients. Objective To explore the perspectives of various leaders in health care about the current and potential contributions of community pharmacists to patients on ADT. Setting The province of Quebec (Canada). Method We conducted a qualitative descriptive exploratory study using interviews among leaders who were involved in health care services, pharmaceutical services, physician and pharmacist education, as well as patient and healthcare professional associations. Verbatim transcripts of interviews were analyzed using computer-assisted thematic analysis. Main outcome measure Perspectives about the contributions of community pharmacists to patients on ADT. Results Interviews revealed that pharmacists are perceived to be accessible drug experts whose particular strengths are their thorough knowledge of drugs, their commitment to ensure ADT safety and tolerability, as well as their commitment to inform and support patients. Leaders trained in pharmacy or representatives of pharmacy organizations had concrete expectations for pharmacists' increased involvement in monitoring ADT adherence and efficacy. They extensively discussed the regulatory and organizational changes required to enhance this role. Leaders also stated that, in addition to patients, health care teams could benefit from pharmacists' expertise and support. Conclusion Participating key informants perceived the need for enhanced pharmacist monitoring of ADT adherence and efficacy. They also expressed their openness to an increased collaboration between health care teams and pharmacists. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether there is an association between antidepressant use and the risk of developing type 2 diabetes. Methods: This study was a retrospective cohort analysis using the Texas Medicaid prescription claims database. Data were extracted for new users of either antidepressant agents (exposed) or benzodiazepines (unexposed) from January 1, 2002 through December 31, 2009. Patients aged 18-64 years without a prior history of diabetes were included. Cox proportional hazards regression was used to examine the association between diabetes incidence among exposed and unexposed groups, while controlling for demographic and clinical covariates. Results: Among the total study population ( N = 44,715), the majority were in the exposed ( N = 35,552) versus the unexposed ( N = 9,163) group. A total of 2,943 patients (6.6%) developed type 2 diabetes during the follow-up period. Antidepressant use was associated with an increase in the risk of diabetes when compared to benzodiazepine use (adjusted hazard ratio [HR] 1.558, 95% confidence interval [CI] 1.401-1.734). The association was observed with tricyclic antidepressants (TCAs; HR 1.759, 95% CI 1.517-2.040), serotonin-norepinephrine reuptake inhibitors (SNRIs; HR 1.566. 95% CI 1.351-1.816), selective serotonin reuptake inhibitors (SSRIs; HR 1.481, 95% CI 1.318-1.665), and 'other' antidepressants (HR 1.376; 95% CI 1.198-1.581). Conclusions: The results of this study suggest that antidepressant use is associated with an increased risk of diabetes. This association was observed with use of TCAs, SNRIs, SSRIs, and 'other' antidepressants. [ABSTRACT FROM AUTHOR]

im of the review Although there are several case reports in literature linking use of antidepressants and disturbances in glucose control, it is difficult to identify risk factors for serious adverse drug events from individual case reports. The aim of this review is to provide a descriptive analysis of the demographic and clinical characteristics of published glucose dysregulation case reports following initiation of antidepressant agents. Methods Published case reports of glucose dysregulation associated with antidepressants were accessed through PubMed (Medline), PsycINFO, and Web of Science (WOS) between January 1, 1970 and April 30, 2010. The following key words were used: antidepressant agents, glucose dysregulation, hypoglycemia, hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Case reports were excluded if glucose dysregulation occurred after a drug overdose/improper dosing or after the patient was prescribed drugs known to cause glucose disturbances in addition to antidepressant agents. Results Out of the 17 cases reports reviewed, nine (53%) were of hyperglycemia while eight (47%) were of hypoglycemia. Hyperglycemia was reported following treatment with clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline. Hypoglycemia was reported following treatment with doxepine, fluoxetine, imipramine, nefazodone, nortriptyline, maprotiline, and sertraline. Fourteen out of the seventeen patients were female (82%) while ten had a history of diabetes mellitus (59%). The average age of the patients was 53.9 (SD = 17.5) years (range: 24-84 years). The time to onset of glucose dysregulation ranged from 4 days to 5 months after initiation of antidepressant therapy. More than two-thirds (68%) of the cases (n = 11) reported glucose control disturbances within 1 month of therapy. Conclusions It is not clear from published case reports whether changes in glucose regulation, following antidepressant therapy initiation are due to antidepressants or changes in mood and lifestyle. Nonetheless, healthcare providers should be aware of the potential changes in glucose regulation especially in the first month of antidepressant therapy, and use appropriate clinical and laboratory monitoring to prevent serious adverse events in patients at risk. [ABSTRACT FROM AUTHOR]

Stimulant medications are the most effective drugs in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and in adults. However, some patients do not respond to this treatment and other patients suffer from adverse effects. Very often there are also comorbid disorders that warrant treatment or there is somatic comorbidity that precludes the prescription of stimulants. As a result, alternative treatments for the treatment of ADHD have been explored, such as antidepressant agents. In this systematic review the evidence base for the effect of antidepressants for ADHD in adult patients is determined. Electronic and hand searches were conducted in order to identify clinical trials studying antidepressants for the treatment of ADHD in adult patients. The trials were screened for methodological characteristics and treatment-effect sizes. The odds ratio was calculated for randomized controlled trials with bupropion. A descriptive review of all the randomized controlled studies and an overview of the nonrandomized studies was developed. Only eight randomized controlled trials were retrieved with four different compounds. Five studies concerned bupropion and the meta-analysis indicates a beneficial effect for bupropion compared with placebo as measured with the Clinical Global Improvement Scale (odds ratio 2.42 [95% CI 1.09 to 5.36]). Several studies suffer from clinical and methodological shortcomings, such as exclusion of patients with comorbid disorders, short treatment duration, or a lack of information with respect to the randomization procedure. Although there is a need for alternative interventions for the treatment of ADHD, such as with antidepressant agents, the evidence base is not large. Only treatment with bupropion seems to have a medium-range effect size, but this is less than that of stimulant medications. [ABSTRACT FROM AUTHOR]

Antidepressants increase synaptic monoamine concentrations, but the subsequent signaling events that produce the beneficial clinical effects remain unclear. Diverse antidepressants increase CDP-diacylglycerol, a crucial step in phosphoinositide signaling. Serotonin 5HT2 receptors, implicated in depression or the actions of some antidepressants, signal through phosphoinositide hydrolysis. Thus, cross talk between antidepressant-induced CDP-diacylglycerol and 5HT2 signaling could contribute to the antidepressant mechanism. The objective of the study was to test the hypotheses that antidepressants enhance net signaling via 5HT2 receptors by augmenting the supply of phosphoinositide substrates and that this action contributes to the behavioral effects of the drugs. Brain slices pre-labeled with [3H]inositol in the presence of various antidepressant concentrations were washed and incubated with the 5HT2 agonist, α-methylserotonin, followed by measuring phosphoinositide synthesis and inositol phosphate accumulation. Further, rats administered antidepressants after pretreatment with neomycin to inhibit metabolic utilization of phosphoinositides were behaviorally evaluated in the forced swim test. Diverse antidepressants significantly enhanced phosphoinositide synthesis. While α-methylserotonin increased inositol phosphate accumulation, this effect was significantly accentuated in hippocampal or cortical tissues pre-incubated in the presence of imipramine, desipramine, fluoxetine, paroxetine, or maprotiline. Drug-induced behavioral antidepressant effects were reversed by neomycin pretreatment, whereas neomycin alone did not alter basal immobility times. Antidepressants probably exert tandem neurochemical effects by increasing synaptic monoamine concentrations and by producing phosphoinositides used in 5HT2 receptor signaling. This combination of actions may constitute the mechanism of at least the acute behavioral effects of the drugs and could implicate aberrant neurolipid signaling in the pathophysiology of depression. [ABSTRACT FROM AUTHOR]

Although associations have been reported between antidepressant use and risk of breast cancer, the findings have been inconsistent. We conducted a population-based case-control study among women enrolled in Group Health Cooperative (GHC), a health maintenance organization in Washington State. Women with a first primary breast cancer diagnosed between 1990 and 2001 were identified (N = 2904) and five controls were selected for each case (N = 14396). Information on antidepressant use was ascertained through the GHC pharmacy database and on breast cancer risk factors and screening mammograms from GHC records. Prior to one year before diagnosis of breast cancer, about 20% of cases and controls had used tricyclic antidepressants (adjusted odds ratio = 1.06, 95% CI 0.94-1.19) and 6% of each group had used selective serotonin reuptake inhibitors (OR = 0.98, 95% CI 0.80-1.18). There also were no differences between cases and controls with regard to the number of prescriptions filled or the timing of use. Taken as a whole, the results from this and other studies to date do not indicate an altered risk of breast cancer associated with the use of antidepressants overall, by class, or for individual antidepressants. [ABSTRACT FROM AUTHOR]

The demetylation of imipramine and clomipramine was studied after administration by different routes of single doses of clomipramine hydrochloride and multiple doses of clomipramine as well as imipramine hydrochloride. Five healthy volunteers received 1 mg of clomipramine hydrochloride/kg body weight as single oral and intramuscular doses on different occasions for the purpose of studying the plasma levels of clomipramine and the desmethylclomipramine formed. Desmethyl-clomipramine was found in the plasma in four of the subjects after oral intake but only in one subject after intramuscular injection. The peak levles of clomipramine were considerably higher after intramuscular than after oral administration. The half-lives of clomipramine after oral administration ranged from 11.6-35.8 h $$\bar M = 20.8 \pm 4.0$$ and after intramuscular administration from 20.1-39.6 h $$\bar M = 24.7 \pm 3.7$$ . Twenty subjects received either imipramine or clomipramine both orally and intramuscularly during a period of 3 weeks in a crossover design. The plasma levels of imipramine and clomipramine and their demethylated metabolites desipramine and desmethyl-clomipramine were determined during the treatment. The ratio between the plasma level of the parent drug and its demethylated metabolite was on average twice as high during intramuscular as during oral treatment. [ABSTRACT FROM AUTHOR]

The EEG and MUA (multiple unit activity) of mesencephalic reticular formation (MRF), area hypothalami posterior (PH), and area hypothalami anterior (AH) were studied in chronically implanted freely moving cats. The effects of thyrotropin-releasing hormone (TRH) and some antidepressant agents were tested on neuronal activity. Desipramine and imipramine resulted in a dose-dependent decline of MUA of all structures with the most significant decrease of activity in PH. A single injection of TRH resulted in slight or moderate gross behavioral changes and vegetative excitation lasting for 30-50 min with variable MUA levels. In the course of repetitive TRH treatment on consecutive days the gross behavioral changes and the vegetative symptoms failed to develop by the 3rd or 4th day. By that time the MUA changes of PH and MRF showed similar characteristics in response to TRH administration which was observed following the injection of desipramine and imipramine. The drugs, except for TRH, induced a suppression of paradoxical sleep cycles. [ABSTRACT FROM AUTHOR]

Evaluation of the efficacy of antidepressant agents needs to take into account factors which increase the 'effect size', such as dosage, treatment duration, the use of two-phase trials, and pattern analysis of responders. Although many patients are thought to receive inadequate doses of antidepressants, relatively few dose-response studies have been performed. However, trials of both tricyclic antidepressants and phenelzine have shown that statistically significant improvements in outcome result from the use of higher dosages; the length of treatment may also affect results. In some studies, the proportion of patients showing a clear-cut response increased significantly among patients treated with active drug instead of placebo when the treatment period was extended from 4 to 6 weeks, independent of the dose used. There may thus be a distinct advantage in extending trials of antidepressants for a minimum of 6 weeks. Two-phase drug trials can be used to extend the trial period still further in responding patients, to emphasise the contrast between treatment and placebo effects and to eliminate type-2 errors. Twelve-week trials might increase the statistical power of the evaluation by 10-20%, in studies where the drug effect size is small. Pattern analysis of the timing and duration of patients' responses has been shown to aid the distinction of true responses from non-specific or placebo effects, and may be useful for evaluating data from studies of antidepressant agents which yield ambiguous results. [ABSTRACT FROM AUTHOR]

We report the case of a male individual who developed a severe photosensitive reaction after sun exposure during therapy with fluoxetin 20 mg bid plus alprazolam 0.25 mg bid due to depressive disturbances. The patients, of North African origin, was not taking other prescription medications nor over the counter products; in the past he had never shown any reaction to sunlight nor had ever used sun protective agents because of its phenotypical skin mark. Three months later, after a second photosensitive reaction, the pharmacological therapy was finally discontinued. [ABSTRACT FROM AUTHOR]