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Latest Results for Psychopharmacology

Thursday, December 4, 2014

December 2014

Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study

Journal of Psychiatric Research

Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33–36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.


Best Treatment Options for Bipolar Depression

Acta Psychiatrica Scandinavica


Treatment of bipolar depression is complicated by variable response and risk of switch to mania. Guidance is informed by the strength of evidence rather than by comparative data.

We performed a multiple-treatments meta-analysis of randomised, double-blind, controlled comparisons of 4–16 weeks in adults in bipolar depression. The primary efficacy outcome was effect size. The primary acceptability outcome was ‘switch to mania’. Secondary outcomes were likelihood of response and withdrawals from trials.

Twenty-nine studies were included (8331 participants). Olanzapine + fluoxetine and olanzapine performed best on primary outcome measure being ranked highest for effect size. Switch to mania was least likely with ziprasidone and then quetiapine. Olanzapine + fluoxetine was also ranked the highest for response with lurasidone second, but olanzapine + fluoxetine and olanzapine had the optimal effect on response and withdrawal from treatment when the two parameters were considered together. Several treatments [monoamine oxidase inhibitors (MAOIs), ziprasidone, aripiprazole and risperidone] have limited or no therapeutic activity in bipolar depression.

Olanzapine + fluoxetine should be first-line treatment. Olanzapine, quetiapine, lurasidone, valproate and selective serotonin re-uptake inhibitors are also recommended. Tricyclic antidepressants and lithium are worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole and risperidone (no evidence of efficacy) should not be used.


Potential Biomarker for Alcohol-Dependence Drug Identified

Translational Psychiatry


Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10−5). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.


Intranasal Oxytocin: The End of Fear?

Biological Psychiatry Journal


Current neurocircuitry models of anxiety disorders posit a lack of inhibitory tone in the amygdala during acquisition of Pavlovian fear responses and deficient encoding of extinction responses in amygdala-medial prefrontal cortex (mPFC) circuits. Competition between these two responses often results in a return of fear, thus limiting control over anxiety. However, one intriguing hypothesis holds that a pharmacological strategy aimed at reducing amygdala activity while simultaneously augmenting mPFC function could facilitate the extinction of conditioned fear.

Key among the endogenous inhibitors of amygdala activity in response to social fear signals is the hypothalamic peptide oxytocin. To address the question whether oxytocin can strengthen Pavlovian extinction beyond its role in controlling social fear, we conducted a functional magnetic resonance imaging (fMRI) experiment involving 62 healthy male participants in a randomized, double-blind, parallel group, placebo-controlled design. Specifically, subjects were exposed to a Pavlovian fear conditioning paradigm before receiving a intranasal dose (24 IU) of synthetic oxytocin or placebo.

We found that oxytocin, when administered intranasally after Pavlovian fear conditioning, increases electrodermal responses and PFC signals to conditioned fear in the early phase of extinction and enhances the decline of skin conductance responses in the late phase of extinction. Furthermore, oxytocin evokes an unspecific inhibition of amygdalar responses in both phases.

Collectively, our findings identify oxytocin as a differentially acting modulator of neural hubs involved in Pavlovian extinction. This specific profile of oxytocin action may open up new avenues for enhancing extinction-based therapies for anxiety disorders.


Long-term Cell Phone Use Linked to Brain Tumor Risk

Pathophysiology Journal


We made a pooled analysis of two case-control studies on malignant brain tumours with patients diagnosed during 1997–2003 and 2007–2009. They were aged 20–80 years and 18–75 years, respectively, at the time of diagnosis. Only cases with histopathological verification of the tumour were included. Population-based controls, matched on age and gender, were used. Exposures were assessed by questionnaire. The whole reference group was used in the unconditional regression analysis adjusted for gender, age, year of diagnosis, and socio-economic index. In total, 1498 (89%) cases and 3530 (87%) controls participated. Mobile phone use increased the risk of glioma, OR = 1.3, 95% CI = 1.1–1.6 overall, increasing to OR = 3.0, 95% CI = 1.7–5.2 in the >25 year latency group. Use of cordless phones increased the risk to OR = 1.4, 95% CI = 1.1–1.7, with highest risk in the >15–20 years latency group yielding OR = 1.7, 95% CI = 1.1–2.5. The OR increased statistically significant both per 100 h of cumulative use, and per year of latency for mobile and cordless phone use. Highest ORs overall were found for ipsilateral mobile or cordless phone use, OR = 1.8, 95% CI = 1.4–2.2 and OR = 1.7, 95% CI = 1.3–2.1, respectively. The highest risk was found for glioma in the temporal lobe. First use of mobile or cordless phone before the age of 20 gave higher OR for glioma than in later age groups.


Stress and Depression Mediated by Single Brain Protein: β-catenin mediates stress resilience through Dicer1/microRNA regulation.



β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1—important in small RNA (for example, microRNA) biogenesis—as a β-catenin target gene that mediates resilience. Small RNA profiling after excising β-catenin from nucleus accumbens in the context of chronic stress reveals β-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish β-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.


Vortioxetine in the treatment of adult patients with major depressive disorder: a meta-analysis of randomized double-blind controlled trials.

BMC Psychiatry


Vortioxetine is a novel multimodal compound that has recently been approved by the FDA for the treatment of major depressive disorder (MDD). It is a selective serotonin (5-HT) 3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of serotonin transporters. The objective of this meta-analysis was to evaluate the efficacy and safety of vortioxetine in adults with MDD.

A literature search was conducted in the databases of PubMed, EMBASE, Cochrane library and HINARI. The meta-analysis was conducted by including randomized controlled trials that assessed the efficacy and safety of vortioxetine in adult patients with MDD. Using the random effects model, which assumes individual studies are estimating different treatment effects, the efficacy and safety of vortioxetine was determined by weighted mean differences (WMDs) and odds ratios (ORs). The findings were considered as statistically significant when the 95% CI of WMDs and ORs did not include 0 and 1, respectively. Heterogeneity testing, meta-regression and sensitivity analysis were also performed.

During the initial literature search about 151 publications were identified. Based on the predetermined inclusion criteria, 7 randomized controlled trials were included. The pooled analysis demonstrated a statistically significant reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score from baseline among patients who were on vortioxetine (WMD = −3.92; 95% CI, −5.258 to −2.581). Furthermore, a statistically significant number of patients with MDD who were on vortioxetine have achieved a greater than or equal to 50% reduction in depression symptoms from baseline. However, a significant number of patients who were on vortioxetine therapy reported more adverse events than patients who were on placebo (overall OR = 1.21; 95% CI, 1.06 to 1.38).

Therapy with vortioxetine was significantly associated with reduction in depression symptoms from baseline compared to placebo. Nevertheless, a significant number of patients who were on vortioxetine therapy have reported more adverse events.


Could a Parasite Lead to Schizophrenia?

PsychCongress Network

Approximately one-fifth of schizophrenia cases may be related to infection with Toxoplasma gondii, a parasite that infects just over 20% of the US population and is found in cat feces and undercooked food.

Most individuals infected with t. gondii are not aware of the infection, but the parasite is present in the brain and muscles. Research has suggested an association with schizophrenia and with changes in behavior and personality.

“Although the claim that infection with T. gondii is one of the component causes of a diagnosis of schizophrenia remains contentious, it is worth asking how important a causal association might be if only to inform our attitude to further work on the subject,” wrote Gary Smith, MA, DPhil, professor of population biology and epidemiology at the University of Pennsylvania’s School of Veterinary Medicine. Dr. Smith published a study in Preventive Veterinary Medicine.

For the current study, Dr. Smith used the population attributable factor (PAF), which describes the proportion of schizophrenia diagnoses that would not occur in a population without T. gondii infections.

However, conventional estimation methods were not possible because they do not account for certain variables, such as how T. gondii infection increases with age. Instead, Dr. Smith used a deterministic model of infection and schizophrenia occurrence in a hypothetical cohort of people at risk for both conditions.

“Under these circumstances, the life-time mean population attributable fraction was estimated to be 21.4%, but it could not be ruled out that it could be as high as 30.6% or as low as 13.7% given the 95% confidence interval pertaining to the point estimate of the OR that was central to the calculation,” Dr. Smith stated.

Thus, prevention of T. gondii infection during a lifetime may prevent one-fifth of cases of schizophrenia, Dr. Smith explained. “That, to me is significant,” he added.

“By finding out how important a factor T. gondii infection is, this work might inform our attitude to researching the subject,” Dr. Smith said. “Instead of ridiculing the idea of a connection between T. gondii and schizophrenia because it seems so extraordinary, we can sit down and consider the evidence. Perhaps then we might be persuaded to look for more ways to reduce the number of people infected with Toxoplasma.”

—Lauren LeBano


Neurobehavioral Markers of Recurrence After Early Childhood Major Depressive Disorder

JAMA Psychiatry


This is the first study to date to examine volumetric alterations in the anterior insula (AI) as a potential biomarker for the course of childhood major depressive disorder (MDD).

To examine whether children with a history of preschool-onset (PO) MDD show reduced AI volume, whether a specific symptom of PO MDD (pathological guilt) is related to AI volume reduction (given the known relationship between AI and guilt processing), and whether AI volumes predict subsequent likelihood of having an episode of MDD.

Design, Setting, and Participants  
In a prospective longitudinal study, 306 children (age range, 3.00-5.11 years) and caregivers completed DSM diagnostic assessments at 6 annual time points during 10 years as part of the Preschool Depression Study. Magnetic resonance imaging was completed on a subset of 145 school-age children (age range, 6.11-12.11 years).

Main Outcomes and Measures
Whole-brain–adjusted AI volume measured using magnetic resonance imaging at school age and children’s diagnosis of MDD any time after their imaging.

Compared with children without a history of PO MDD, school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes (Wilks Λ = 0.94, F2,124 = 3.37, P = .04, Cohen d = 0.23). However, the effect of PO MDD on reduced AI volumes was better explained by children’s experience of pathological guilt during preschool (Λ = 0.91, F2,120 = 6.17, P = .003, d = .30). When covarying for children’s lifetime history of MDD episodes, their experience of pathological guilt during preschool, as well as their sex and age at the time of imaging, schoolchildren’s right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging (odds ratio, 0.96; 95% CI, 0.01-0.75; P = .03).

Conclusions and Relevance  
These results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood. The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression.


FDA Approves Antipsychotic for Schizoaffective Disorder Treatment

TITUSVILLE, N.J., Nov. 13, 2014 /PRNewswire/ -- Janssen Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Applications (sNDAs) for the once-monthly atypical long-acting antipsychotic INVEGA® SUSTENNA® (paliperidone palmitate) to treat schizoaffective disorder as either monotherapy or adjunctive therapy. The symptoms of schizoaffective disorder are complex and, without treatment, disabling. The FDA approved these sNDAs under priority review, which is a designation for drugs that, if approved, would offer significant improvement in the treatment of serious conditions.

INVEGA® SUSTENNA® is the first and only FDA-approved once-monthly medication to treat schizoaffective disorder as monotherapy.

"Clinicians often find themselves taking a complicated approach using multiple medications to address schizoaffective disorder symptoms because widely accepted guidelines for the treatment of the condition are not available," said David P. Walling, PhD, study lead investigator and Chief Executive and Clinical Officer, Collaborative NeuroScience Network, Inc., Los Angeles. "The approval of an effective once-monthly medication that can be used as monotherapy or adjunctive therapy to manage the symptoms associated with schizoaffective disorder has the potential to change that approach."

The approval is based on data from a 15-month period of a long-term maintenance study measuring ability to delay relapse in schizoaffective disorder. The study found that treatment with INVEGA® SUSTENNA® resulted in a statistically significant delay in relapse due to mood (depression and mania) and psychotic symptoms of schizoaffective disorder compared to placebo. Results of the study were presented in May at the 167th Annual Meeting of the American Psychiatric Association.

"Schizoaffective disorder is a difficult-to-treat disease. Approval of INVEGA® SUSTENNA® to manage the mood as well as the psychosis that define the condition has the potential to change the lives of the 750,000 adult Americans who suffer from it," said Dong-Jing Fu, MD, PhD, Director of Clinical Development at Janssen Scientific Affairs, LLC. "Janssen is proud to expand treatment options for those living with schizoaffective disorder and to provide new possibilities for the family members and friends who care for them."

Few large, controlled studies have systematically studied the clinical characteristics of schizoaffective disorder and long-term treatment options. This study, which included a 6-month open-label treatment period and a 15-month double-blind period, was the first registration trial to study maintenance treatment of a long-acting injectable in this complex disease. In addition to the approval of INVEGA® SUSTENNA® as monotherapy for schizoaffective disorder, it is approved as adjunctive therapy to mood stabilizers or antidepressants.

The most common INVEGA® SUSTENNA® adverse reactions, defined by at least a 5% incidence and twice that of placebo, are injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. No occurrences of these adverse events reached this threshold in this study of patients with schizoaffective disorder.


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