Serotonin-norepinephrine Reuptake Inhibitor Venlafaxine Research Articles

A retrospective study on the clinical use and owner perception of venlafaxine efficacy as part of a multimodal treatment for canine fear, anxiety, and aggression

The serotonin-norepinephrine reuptake inhibitor venlafaxine is labeled for use in the treatment of several emotional disorders in people and has been steadily growing in popularity for the treatment of aggression, anxiety, and fear-related behavior problems in canine patients. Current publications describing the clinical use of venlafaxine in dogs are limited to a narcolepsy-cataplexy case report and its suggested use for pain and narcolepsy. In this retrospective open-label clinical trial, the records for dogs administered venlafaxine for a minimum of 21 days in combination with an individual management and behavior modification plan for the treatment of fear, anxiety, and aggressive behaviors were reviewed. The following factors were considered: owner-reported efficacy, dose range, diagnosis, number of diagnoses, and previously trialed and concurrent medications. Of the 110 dogs included, 71.8% (N = 79) percent of owners reported venlafaxine as helpful during at least one follow-up and 39.1% (N = 43) found it helpful at all three follow-up points. For those who found it helpful, the median dose used was 1.65 mg/kg by mouth every 12 hours (range 0.63-5.91 mg/kg every 12 hours). Venlafaxine was not more helpful in treating any specific diagnosis or number of diagnoses. Due to the efficacy and low frequency of adverse effects (N = 20, 18.2%), venlafaxine might be a useful medication option in dogs showing clinical signs of aggression, anxiety, and fear.

The Efficacy and Safety of Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors in the Treatment of Menopausal Hot Flashes: A Systematic Review of Clinical Trials.

Background: Hot flashes (HF) are a common symptom during the menopausal transition. It is therefore important to identify effective drugs that can alleviate HF. This study aimed to systematically review published clinical trials on the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in the treatment of HF in healthy menopausal womenMethods: In this systematic review, articles published during 2003-2019 in PubMed, MEDLINE, Web of Science, Scopus, Science Direct, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, and Google Scholar as well as Iranian databases such as SID, and Magiran were searched. The quality of the selected articles was assessed using the Jadad score calculation.Results: Thirty-six articles on randomized controlled trials were included in this study, out of which 27 articles had acceptable, and nine had weak methodological quality. Findings on SSRIs class of drugs indicated that escitalopram, paroxetine, and fluoxetine have higher efficacy and safety in the treatment of menopausal HF than other drugs. Studies on the effectiveness of sertraline, citalopram, and fluvoxamine are limited in number or show inconsistent results. Therefore, further high-quality studies are required to confirm their effectiveness in alleviating HF. Within the SNRIs class, venlafaxine and desvenlafaxine showed significant efficacy in the treatment of menopausal HF. However, studies on the effectiveness of duloxetine are also limited, which requires further research.Conclusion: Most studies have indicated the efficacy and safety of some antidepressants, such as SSRIs and SNRIs, in decreasing the frequency and severity of HF. These drugs are therefore recommended for the treatment of menopausal HF.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Visualizing Patterns of Medication Switching Among Major Depressive Patients with Various Stability and Difficulty to Treatments.

IntroductionEfforts have been made in assessing efficacy and tolerability to various antidepressants, but understanding personalized chances of stability to medication switching sequence is still inconclusive. This study aimed to identify naturalistic switching patterns of medication in stratifying MDD patients.MethodsMDD patients were stratified based on treatment difficulty evaluated with the “Treatment Resistance to Antidepressants Evaluation Scale for Unipolar Depression” (TRADES). The duration of the time of diagnoses until the final switch to another class of antidepressants was used as prediction of unstable to drug therapy. ROC analysis was used to determine the cutoff values. A continuous temporal events function from the visual analytic tool was employed to perform patterns of switching between distinct pharmacological class such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).ResultsTRADES scores of 4.5 and not-switching times of 12.5 months were used as cutoff values to divide patients into four subgroups: stable/easy-to-treat (SE), unstable/easy-to-treat (UE), stable/difficult-to-treat (SD) and unstable/difficult-to-treat (UD). A total of 80% and 76.9% of patients initially treated with the SSRIs paroxetine or fluoxetine, respectively, were predicted to be stable to drug therapy. Approximately 70%, 44.8% and 41.4% of patients initially treated with the SNRIs fluvoxamine, sertraline and venlafaxine, respectively, were predicted to be UD, and 60% of patients using duloxetine were predicted to be stable to drug therapy. Analysis of the switching phenomenon showed that SSRIs were the first prescribed medications and mostly taken by the stable subgroups, and SNRIs were the preferentially chosen switching alternative. Medication switching patterns in unstable MDD patients are discussed.ConclusionParoxetine, fluoxetine and duloxetine users were mostly stable among MDD patients in Taiwan with various stability and difficulty to treatments. Although responsiveness to specific medication sequence is likely required for clinical application, the results provide a baseline for such studies.

Post-traumatic Stress Disorder in Middle Age and Beyond.

To review the clinical manifestations and treatment of post-traumatic stress disorder (PTSD) in adults and older people. Articles indexed in PubMed, Embase, psychology databases, and the Cochrane library over the past 10 years using the key words "post-traumatic stress disorder," "stress disorders," and "post-traumatic stress disorder and treatment." Sixty-seven publications were reviewed and criteria supporting the primary objective were used to identify useful resources. The literature included practice guidelines; review articles; original research articles; and product prescribing information for the clinical manifestations, diagnosis, and treatment of PTSD. Psychotherapy is the first-line therapy for PTSD. Pharmacologic therapy is recommended, as second-line therapy, for adults living with PTSD who do not have access to psychotherapy or refuse psychotherapy. Pharmacologic therapy may also be considered in cases of partial, or no, response to psychotherapy. Current guidelines recommend prescribing one of 3 selective serotonin-reuptake inhibitors, either fluoxetine, paroxetine, or sertraline, or prescribing the serotonin norepinephrine reuptake inhibitor venlafaxine, for adult patients who do not have access to psychotherapy or prefer not to use psychotherapy. Unfortunately, these recommended medications have additional cautions for use in older people so may not be appropriate for many older people living with PTSD. Therapy for older people should be tailored to patient-specific symptoms, with careful consideration of the potential benefits and risks of the therapy and coexisting medical conditions of each patient.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

BackgroundSelective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants.MethodsPrimary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed.ResultsAll the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity.ConclusionsThe study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

No association between CYP2C19 genetic polymorphism with treatment remission to antidepressant venlafaxine in Han Chinese population.

Major depressive disorder (MDD) is a global mental health problem. As a serotonin-noradrenaline reuptake inhibitor (SNRI), the antidepressant venlafaxine is used to alleviate MDD clinically. Recent research has shown that Cytochrome P450 (CYP) enzymes affect venlafaxine efficacy by mediating its metabolism. The present study investigates genetic polymorphisms of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) are associated with remission after venlafaxine treatment for MDD. A total of 175 Han Chinese patients with depression were recruited to accept a 6-week treatment with venlafaxine. Three single-nucleotide polymorphisms of CYP2C19 were selected from dbSNP and previous literature to compare the allele and genotype frequencies between patients in remission and nonremission. Seventeen items Hamilton Depression Scale (17-HAMD) was used to access the outcomes of patients' depressive symptoms through the study. Our results denied the role of CYP2C19 polymorphisms for remission after venlafaxine treatment in MDD patients. CYP2C19 genetic polymorphism may not have association with SNRI venlafaxine treatment remission in the Han Chinese population.

Upregulation ofantioxidant thioredoxin by antidepressants fluoxetine andvenlafaxine.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used drugs for the treatment of depression. Studies have shown that chronic treatment with SSRIs and SNRIs produces a protective effect against oxidative stress. Thioredoxin (Trx) is an antioxidant protein that reverses protein cysteine oxidation and facilitates scavenging reactive oxygen species. The current study is to determine whether the SSRI fluoxetine and the SNRI venlafaxine regulate Trx and protect neuronal cells against protein cysteine oxidation. HT22 mouse hippocampal cells were incubated with fluoxetine or venlafaxine for 5days. Protein levels of Trx, Trx reductase (TrxR), and Trx-interacting protein (Txnip) were measured by immunoblotting analysis. Trx and TrxR activities were analyzed by spectrophotometric method. Protein cysteine sulfenylation was measured by dimedone-conjugation assay, while nitrosylation was measured by biotin-switch assay. We found that treatment with fluoxetine or venlafaxine for 5days increased Trx and TrxR protein levels but produced no effect on Txnip protein levels. These treatments also increased Trx and TrxR activities. Although treatment with fluoxetine or venlafaxine alone had no effect on sulfenylated and nitrosylated protein levels, both drugs inhibited H2O2-increased sulfenylated protein levels and nitric oxide donor nitrosoglutathione-increased nitrosylated protein levels. Stress increases risk of depression. We also found that treatment with fluoxetine or venlafaxine for 5days inhibited stress hormone corticosterone-increased total sulfenylated and nitrosylated protein levels. Our findings suggest that chronic treatment with antidepressants may upregulate Trx, subsequently inhibiting protein sulfenylation and nitrosylation, which may contribute to the protective effect of antidepressants against oxidative stress. Our findings also indicate that thioredoxin is a potential therapeutic target for the treatment of depression.

Pharmacotherapy for Hoarding Disorder: How did the Picture Change since its Excision from OCD?

This brief review deals with the various issues that contributed to the creation of the new Diagnostic and Statistical Manual condition of hoarding disorder (HD) and attempts at reviewing its pharmacotherapy. It appears that after the newly founded diagnosis appeared in the literature as an autonomous entity, distinct from obsessive-compulsive disorder, drug trials are not being conducted and the disorder is left in the hands of psychotherapists, who on their part, report fair results in some core dimensions of HD. The few trials on HD specifically regard the serotonin-noradrenaline reuptake inhibitor venlafaxine, and, possibly due to the suggestion of a common biological background of HD with attention-deficit/hyperactivity disorder, the psychostimulant methylphenidate and the noradrenaline reuptake inhibitor atomoxetine. For all these drugs, positive results have been reported, but the evidence level of these studies is low, due to small samples and non-blind designs. Regretfully, there are currently no future studies aiming at seriously testing drugs in HD.

Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.

Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials. The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression. The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes. These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults.

This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache. To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults. For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache. Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period. The original review included six studies on tension-type headache. We now include eight studies with a total of 412 participants with chronic forms of tension-type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow-up ranged between two and four months.Six studies explored the effect of SSRIs or SNRIs on tension-type headache frequency, the primary endpoint. At eight weeks of follow-up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) -0.96, 95% confidence interval (CI) -3.95 to 2.03; I(2)= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI -2.05 to 3.57; I(2)= 44%).When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD -1.87, 95% CI -2.09 to -1.65; I(2)= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I(2)= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity.SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I(2)= 25% and OR 1.55, 95% CI 0.71 to 3.38; I(2)= 0%).We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non-drug therapies (e.g. psycho-behavioural treatments, manual therapy, acupuncture). Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine (a SNRI) as preventive drugs for tension-type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension-type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow-up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension-type headache is not supported by evidence.

Antidepressant May Have Role in Treating Menopause Symptoms

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAntidepressant May Have Role in Treating Menopause SymptomsJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:17 Jul 2014https://doi.org/10.1176/appi.pn.2014.7a6AbstractWhen menopausal women cannot or do not want to take estrogen to combat bothersome hot flashes and night sweats, antidepressants may serve as an effective alternative.Although estrogen has long been the gold standard for treating the hot flashes and night sweats of menopause, some women are unable or unwilling to use it because of associated risks. Consequently, SSRI or SNRI antidepressants—particularly the SNRI antidepressant venlafaxine—are often prescribed as a treatment for these vasomotor symptoms.Robert Kneschke/ShutterstockHowever, while SSRI and SNRI antidepressants have been found to be more effective than placebo in countering hot flashes and night sweats, their effectiveness compared with estrogen has not been studied. Hadine Joffe, M.D., an associate professor of psychiatry at Harvard Medical School, and her colleagues conducted a study to evaluate the two types of medications, using venlafaxine as the test antidepressant. As they reported May 26 in JAMA Internal Medicine, both estrogen and venlafaxine were significantly more effective than a placebo, but estrogen was slightly more effective than venlafaxine.A total of 339 perimenopausal and postmenopausal women with at least two bothersome vasomotor symptoms a day—on average, eight a day—took part in the study. The researchers excluded candidates who had experienced major depressive episodes within the previous year.The subjects were randomized to receive either low-dose oral estradiol (0.5 mg/d), low-dose venlafaxine extended release (75 mg/d), or a placebo for eight weeks. The researchers used low-dose rather than high-dose estradiol, they explained, “because of recommendations to use the lowest effective estrogen therapy dosage.”Throughout treatment, and on a daily basis, the subjects recorded in diaries how often they experienced vasomotor symptoms. By the end of treatment, the estradiol group was experiencing 3.9 vasomotor episodes a day on average, the venlafaxine group 4.4., and the placebo group 5.5. Estrogen reduced the frequency of vasomotor episodes by 53 percent, venlafaxine by 48 percent, and placebo by 29 percent. The differences between the estradiol group and the placebo group, as well as between the venlafaxine group and placebo group, were statistically significant. The differences between the venlafaxine group and the estradiol group were not.Tolerability of both estradiol and venlafaxine was high. Discontinuation because of adverse events was uncommon and did not differ significantly between treatments.The researchers also found that the treatment responses were not influenced by subjects’ mood symptoms, sleep quality, or race. A third of the subjects were African American.“It is nice to see this head-to-head study comparing estradiol and venlafaxine in the treatment of menopausal hot flashes,” Claudia Reardon, M.D., an assistant professor of psychiatry at the University of Wisconsin and an expert on women’s health issues, said in an interview with Psychiatric News. “While venlafaxine may not be quite as effective as estradiol in the treatment of these symptoms, it does appear to work notably better than placebo. Our women patients often talk to us as their mental health providers about their bothersome menopausal symptoms, and this study helps us to be able to discuss the likely relative efficacy of their options with them.”“The results of this carefully conducted study provide women and their physicians with critical data to guide treatment for vasomotor symptoms . . . , which affect the lives of the majority of midlife women,” Katherine Wisner, M.D., a professor of psychiatry and obstetrics and gynecology at Northwestern University, told Psychiatric News. “Although a number of studies have demonstrated the efficacy of venlafaxine and other serotonergic antidepressants for treating vasomotor symptoms, this study advances our knowledge by comparing estradiol and venlafaxine to placebo within the same study,” Laura Miller, M.D., medical director of women’s mental health at the Edward Hines Jr. VA Hospital in Illinois, said. “The findings confirm that both estradiol and venlafaxine reduce the frequency, severity, and interference of menopausal hot flashes. While supporting prior impressions that the impact of estradiol on vasomotor symptoms is greater than that of venlafaxine, it shows that the magnitude of difference is relatively small. Caveats are that this study is not a direct comparison between estradiol and venlafaxine (both were compared with placebo) and that medroxyprogesterone was not given during the study as it would be with clinical use of estrogen (it was given only after unblinding). [But] overall, the study adds valuable information about an alternative to estrogen for the treatment of bothersome menopausal vasomotor symptoms.”The study was funded by the National Institutes of Health. ■An abstract of “Low-Dose Estradiol and the Serotonin-Norepinephrine Reuptake Inhibitor Venlafaxine for Vasomotor Symptoms” can be accessed here. ISSUES NewArchived

Methods for the design of vasomotor symptom trials

Objective This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials. Methods Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and ω-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network’s structure and governance are also discussed. Conclusions The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.

Antidepressant-like activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents

RationaleDepression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. ObjectiveWe have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. ResultsIstradefylline significantly decreased immobility time in the FST in both rats and mice (0.16mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. ConclusionsIstradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic–pituitary–adrenal axis.

Differential effects of fluoxetine and venlafaxine on memory recognition: Possible mechanisms of action

Serotonin-specific reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are antidepressant drugs commonly used to treat a wide spectrum of mood disorders (Wong and Licinio, 2001). Although they have been clinically used for more than 50 years, the molecular and cellular basis for the action of SSRIs and SNRIs is not clear. Considering that the changes in gene expression involved in the action of antidepressant drugs on memory have not been identified, in this study we investigated the impact of chronic treatment with a SSRI (fluoxetine) and a SNRI (venlafaxine) on the mRNA expression of genes related to memory cascade in the mouse hippocampus, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nitric oxide synthase 1 (NOS1), neurotrophic tyrosine kinase receptor type 2 (TrKB), mitogen-activated protein kinases (MAPK/ERK) and serotonin transporter (SERT). Animals treated with fluoxetine 10 mg/Kg/day for 28 days showed a significant decrease in the percentage of time spent in the novel object recognition test (p≤0.005) and induced MAPK1/ERK2 down-regulation (p=0.005). Our results suggest that the effect on cognition could probably be explained by fluoxetine interference in the MAPK/ERK memory pathway. In contrast, chronic treatment with venlafaxine did not reduce MAPK1/ERK2 expression, suggesting that MAPK1/ERK2 down-regulation is not a common effect of all antidepressant drugs. Further studies are needed to examine the effect of chronic fluoxetine treatment on the ERK-CREB system, and to determine whether there is a causal relationship between the disruption of the ERK-CREB system and the effect of this antidepressant on memory performance.

Pharmacotherapy for posttraumatic stress disorder: Review with clinical applications

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric diagnosis among veterans and has high comorbidity with other medical and psychiatric conditions. This article reviews the pharmacotherapy recommendations from the 2010 revised Department of Veterans Affairs/Department of Defense Clinical Practice Guideline (CPG) for PTSD and provides practical PTSD treatment recommendations for clinicians. While evidence-based, trauma-focused psychotherapy is the preferred treatment for PTSD, pharmacotherapy is also an important treatment option. First-line pharmacotherapy agents include selective serotonin reuptake inhibitors and the selective serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line agents have less evidence for their usefulness in PTSD and carry a potentially greater side effect burden. They include nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors. Prazosin is beneficial for nightmares. Benzodiazepines and antipsychotics, either as monotherapy or used adjunctively, are not recommended in the treatment of PTSD. Treating co-occurring disorders, such as major depressive disorder, substance use disorders, and traumatic brain injury, is essential in maximizing treatment outcomes in PTSD. The CPG provides evidence-based treatment recommendations for treating PTSD with and without such co-occurring disorders.

Evidence-based pharmacotherapy of panic disorder: an update

The evidence-based pharmacotherapy of panic disorder continues to evolve. This paper reviews data on first-line pharmacotherapy, evidence for maintenance treatment, and management options for treatment-refractory patients. A Medline search of research on pharmacotherapy was undertaken, and a previous systematic review on the evidence-based pharmacotherapy of panic disorder was updated. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder, with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option. Temporary co-administration of benzodiazepines can be considered. Maintenance treatment reduces relapse rates, but further research to determine optimal duration is needed. For patients not responding to first-line agents several pharmacotherapy options are available, but there is a notable paucity of data on the optimal choice.

Comparison of Desvenlafaxine and Venlafaxine Ingestions Reported to Texas Poison Centers

Background: Desvenlafaxine is the major active metabolite of the serotonin norepinephrine reuptake inhibitor venlafaxine and is prescribed for the treatment of major depressive disorder. Objective: To compare desvenlafaxine and venlafaxine ingestions reported to a statewide poison center system. Methods: Cases included all desvenlafaxine and venlafaxine ingestions reported to Texas poison centers during 2008–2009. The distribution of all cases by selected demographic factors was identified. After cases that involved coingestants and/or were not followed to a final medical outcome were excluded, the distribution of the remaining cases by clinical and management factors was determined. Results: There were 144 desvenlafaxine and 777 venlafaxine ingestions. The distribution of desvenlafaxine and venlafaxine ingestions was, respectively, female patients 61.8% versus 64.2%, age 0–5 years 31.9% versus 19.3%, unintentional 47.2% versus 39.8%, and involving no coingestants 56.3% versus 46.7%. There were no coingestants and the medical outcome was known for 47 desvenlafaxine and 208 venlafaxine cases. The distribution of this subset of ingestions was, respectively, managed on site 40.4% versus 24.0%, already at or en route to a health-care facility 36.2% versus 52.9%, and referred to a health-care facility 23.4% versus 23.1%. The medical outcome was no effect 72.3% versus 56.3%, minor 14.9% versus 26.4%, moderate 10.6% versus 14.9%, and major 2.1% versus 2.4% for desvenlafaxine and venlafaxine, respectively. Conclusions: The patterns of desvenlafaxine and venlafaxine ingestions were generally similar. However, desvenlafaxine ingestions were more likely to involve young children, be unintentional, not involve coingestants, be managed on site, and involve no effect.

Venlafaxine-Associated Serotonin Syndrome Causing Severe Rhabdomyolysis and Acute Renal Failure in a Patient With Idiopathic Parkinson Disease

A 43-year-old male patient with idiopathic Parkinson disease, on dopaminergic therapy, was admitted with confusion and agitation, diaphoresis, and hyperkinesia after the commencement of the serotonin-noradrenaline reuptake inhibitor venlafaxine 2 weeks prior for depression. He was found to have severe rhabdomyolysis and developed acute renal failure. The most likely diagnosis was serotonin syndrome induced by venlafaxine, although neuroleptic malignant syndrome was also considered. The differential diagnosis, atypical features in this presentation, and possible mechanisms are discussed.

Efficacy, Safety, and Tolerability of Desvenlafaxine 50 mg/d for the Treatment of Major Depressive Disorder

Desvenlafaxine is the third serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the US Food and Drug Administration for major depressive disorder (MDD). This article summarizes data on the clinical pharmacology, efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) for MDD with a focus on the 50-mg/d therapeutic dose. Additionally, the article discusses clinical practice considerations and future directions in desvenlafaxine research. Data relating to desvenlafaxine 50 mg/d were identified through searches of MEDLINE and publication databases of Pfizer for articles in English published before January 2009. Keywords were desvenlafaxine, O-desmethylvenlafaxine, ODV, and 50 mg. Three randomized, placebo- and/or active comparator-controlled, 8-week clinical trials reported the efficacy of desvenlafaxine 50 mg/d for the treatment of MDD. The third of these studies included a post hoc pooled analysis of data from all 3 of these trials. In addition, the search retrieved an article examining pooled data from 9 trials, including 50-mg data from 2 of the 3 retrieved trials. Desvenlafaxine is the major active metabolite of the SNRI venlafaxine. Significant improvements compared with placebo were observed on the primary efficacy measure (17-item Hamilton Depression Rating Scale total score) and most secondary measures in 2 of 3 clinical trials. An integrated analysis of registration data from 9 randomized, double-blind, placebo-controlled, 8-week studies of desvenlafaxine (50 to 400 mg/d) for MDD demonstrated no evidence of greater efficacy with doses higher than 50 mg/d. Safety results indicate that desvenlafaxine treatment is generally safe and well tolerated; findings were consistent with those for the SNRI class. The 50-mg/d dose of desvenlafaxine was associated with low rates of discontinuation due to treatment-emergent adverse events, which were similar to placebo. Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in placebo-controlled trials. A long-term study is underway to further explore desvenlafaxine 50 mg/d for MDD.