Pimavanserin treatment increases plasma brain-derived neurotrophic factor levels in rats.

Background: Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play a key role in neuroplasticity and neurogenesis. The present study tested the hypothesis that treatment with Pimavanserin is associated with higher and sustained elevations of mBDNF. Methods: Adult Sprague-Dawley male rats were treated with Pimavanserin, Fluoxetine or vehicle for 4 weeks (chronic) or 2 h (acute). BDNF levels were determined by enzyme-linked Immunosorbent assay (ELISA). Results: We found significant increases in plasma mBDNF levels in rats following chronic Pimavanserin treatment, but not in Fluoxetine-treated rats. No significant changes in mBDNF levels were found in the prefrontal cortex or hippocampus following Pimavanserin or Fluoxetine treatment. Conclusion: These findings suggest that increase in mBDNF levels could be a contributing mechanism for the neuroprotective potential of Pimavanserin.

High-dose armodafinil in treatment-refractory bipolar depression.

BACKGROUND: Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major depressive disorder fail to exert efficacy in bipolar depression. Although 5 agents have been developed for the treatment of bipolar depression, treatment resistance is still observed in some patients, and requires off-label pharmacotherapy. Modafinil and armodafinil have been reported to improve treatment-resistant bipolar depression, but with inconsistent results. METHODS: We present a case of a 65-year-old woman with severe bipolar depression who failed to respond to electroconvulsive therapy and IV ketamine but later responded to high-dose armodafanil. RESULTS: The patient responded to high-dose armodafinil (gradually titrated to 1,000 mg/d) and achieved remission with good tolerability for 5 years. Recently, she contracted COVID-19 and developed muscular weakness. After a lengthy workup, we became concerned for myopathy as an adverse effect from armodafinil. The patient's dose of armodafinil was significantly reduced and she subsequently became very depressed and functionally disabled before improving again when armodafinil 1,000 mg/d was reinstated. CONCLUSIONS: We propose that some of the negative results seen in research of armodafinil for bipolar depression may be due to the use of low doses (100 to 200 mg/d), and higher doses may be needed for adequate response in treatment-resistant bipolar depression.

The role of the insula in cognitive impairment of schizophrenia.

Cognitive impairment is one of the core clinical symptom domains of schizophrenia. Research shows that cognitive deficits in this neuropsychiatric syndrome is associated with neurodevelopmental pathology affecting multiple brain regions such as the dorsolateral prefrontal cortex, the hippocampus and the parietal lobe. The insula is a relatively small structure that is highly connected with several brain regions as well as multiple brain networks. A large number of studies have reported the involvement of the insula in many of the psychotic and nonpsychotic manifestations of schizophrenia. Here we review the role of the insula as a hub across key neurocircuits which have been implicated in the various cognitive pathologies in schizophrenia. Structural and functional abnormalities in the right and left insulae may serve as a biomarker for susceptibility to schizophrenia.

The Association of the Gut Microbiota with Clinical Features in Schizophrenia.

The connection between gut microbiota and schizophrenia has become a fertile area of research. The relationship is bidirectional and quite complex, but is likely to lead to practical clinical applications. For example, commensal microbiota have been shown to produce inflammatory metabolites that can cross the blood-brain barrier-a possible neurobiological precursor of psychosis. Antipsychotics that treat these individuals have been shown to alter gut microbiota. On the other hand, life style in schizophrenia, such as diet and decreased exercise, can be disruptive to the normal microbiome diversity. In the present paper, we conduct a review of PubMed literature focusing on the relationship of gut microbiota with clinical symptoms of schizophrenia, which, to our knowledge, has not yet been reviewed. Numerous clinical characteristics were identified correlating to gut microbial changes, such as violence, negative symptoms, treatment resistance, and global functioning. The most consistently demonstrated correlations to gut microbial changes across studies were for the overall symptom severity and negative symptom severity. Although numerous studies found changes in these domains, there is much variability between the bacteria that change in abundance between studies, likely due to the regional and methodological differences between studies. The current literature shows promising correlations between gut microbiota profiles and several clinical features of schizophrenia, but initial studies require replication.

Aripiprazole lauroxil 2-month formulation with 1-day initiation in patients hospitalized for an acute exacerbation of schizophrenia: exploratory efficacy and patient-reported outcomes in the randomized controlled ALPINE study.

BACKGROUND: A randomized, controlled, phase 3b study (ALPINE) evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) using a 1-day initiation regimen in patients hospitalized for an acute exacerbation of schizophrenia. Paliperidone palmitate (PP) was used as an active control. Exploratory endpoint assessments included severity of illness, positive and negative symptoms, quality of life, caregiver burden, and satisfaction with medication. METHODS: Adults were randomly assigned to AL 1064 mg q8wk or PP 156 mg q4wk as inpatients, discharged after 2 weeks, and followed through week 25. Exploratory efficacy measures included the 3 original PANSS subscales, Clinical Global Impression-Severity (CGI-S) subscale, and caregiver Burden Assessment Scale. Exploratory patient-reported outcomes (PROs) included the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Medication Satisfaction Questionnaire. Within-group changes from baseline through week 25 were analyzed for AL and PP separately. PROs were summarized based on observed data. RESULTS: Of 200 patients randomized (AL, n = 99; PP, n = 101), 99 completed the study (AL, n = 56; PP, n = 43). For AL, PANSS subscale and CGI-S scores improved from baseline through week 25 (mean [SE] change from baseline at week 25: Positive, -7.5 [0.70]; Negative, -3.9 [0.46]; General, -11.8 [0.83]; CGI-S, -1.3 [0.12]). Caregiver burden also improved (mean [SD] changes from baseline at week 9: -8.4 [10.15]; week 25: -8.9 [12.36]). Most AL patients were somewhat/very satisfied with treatment at each timepoint (70.8%-74.7%); mean Q-LES-Q-SF total scores were stable in the outpatient period. For PP, results were similar: PANSS Positive, -7.3 (0.67); Negative, -3.6 (0.69); General, -10.9 (1.22); CGI-S, -1.4 (0.16); caregiver burden, week 9: -8.8 (11.89) and week 25: -9.2 (14.55); satisfaction with treatment, 64.7%-69.3%; and stable Q-LES-Q-SF scores. CONCLUSIONS: ALPINE patients initiating the 2-month AL formulation using the 1-day initiation regimen as inpatients and continuing outpatient care experienced schizophrenia symptom improvement, sustained patient satisfaction with medication, stable quality of life, and reduced caregiver burden. A similar benefit pattern was observed for PP. These results support the feasibility of starting either long-acting injectable in the hospital and transitioning to outpatient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03345979 [trial registration date: 15/11/2017].

Measurement-based care training curriculum in psychiatry residency programs: I: Description of the curriculum and demonstration of implementation.

BACKGROUND: Recent literature shows that most practicing psychiatrists do not receive training in measurement-based care (MBC). Among the primary barriers to MBC implementation are the lack of formal training and curriculums. We present the first comprehensive MBC curriculum for use in adult psychiatric practice, and describe how the curriculum is adapted and implemented in psychiatry residency training programs. METHODS: The Standard for Clinicians' Interview in Psychiatry (SCIP) was developed as a measurement-based care tool for clinicians' use. The SCIP is the only instrument that includes 18 reliable and validated clinician-rated scales covering most adult psychiatric disorders. The SCIP has simple, unified rules of measurement that apply to the 18 scales. The MBC curriculum includes 2 instruction manuals, 4 didactic lectures, and 12 videotaped interviews. We describe the annual learning and implementation of MBC curriculum in residency programs. RESULTS: The curriculum implementation at West Virginia University and Delaware Psychiatric Center began in 2019 and is ongoing. We present 3 case demonstrations of the implementation of MBC in clinical settings. CONCLUSIONS: Comprehensive implementation of MBC curriculum in residency programs has the potential to facilitate research and create a "culture" of MBC in future generations of psychiatrists.

The effect of antipsychotic medications on white matter integrity in first-episode drug-naïve patients with psychosis: A review of DTI studies.

BACKGROUND: Psychotic episodes have been associated with damage to both grey matter (GM) and white matter (WM). Although a recent meta-analysis suggest that in long term treatment, first generation antipsychotics (FGA) are associated with progressive reduction in GM, second generation antipsychotics (SGA) seem to have benefits to WM microstructure. METHODS: A search was conducted to identify controlled trials published from January 2000 to January 2021, which assessed WM integrity as measured by DTI in drug-naïve patients with FEP before and after antipsychotic administration. RESULTS: 3 studies met the criteria for inclusion. All studies demonstrated lower FA in psychotic patients vs HC. A 6-week study reported that antipsychotic medication results in a further decrease in FA within the bilateral ACG and right ACR, regions important in emotional processing. An 8-week study found that antipsychotic treatment increase FA in the SLF, resulting in improved symptoms and increased processing speed. A 3rd study found an increase in FA in several regions along with a negative correlation between FA and PANSS at remission. CONCLUSIONS: Drug-naïve FEP patients have WM dysfunction at baseline and antipsychotic medications appear to alter or improve WM especially at remission. More controlled trials are warranted to validate these conclusions.

White matter pathology in patients with borderline personality disorder: A review of controlled DTI studies.

BACKGROUND: Neuroimaging, especially diffusion tensor imaging (DTI), has emerged as a helpful tool in assessing and characterizing white matter (WM) integrity. The resultant early treatment from early diagnosis is crucial because treatment is often more efficacious. Borderline personality disorder (BPD) is a challenging disorder to diagnose and treat, and has been reported to have various neurobiologic abnormalities. We conducted a search of the literature to review WM pathology findings in BPD. METHODS: A search was conducted to identify systematic reviews and meta-analyses published from January 2000 to September 2019 that assessed WM integrity in BPD. RESULTS: Four studies were included. One study demonstrated no difference in WM between BPD and healthy controls. Another study found decreased fractional anisotropy (FA) within the corpus callosum (CC) and orbitofrontal regions. A subsequent randomized controlled trial reported a decrease in FA within the fornix, CC, and right superior/anterior corona radiata with associated increase in radial diffusivity in the left anterior thalamic radiation. The fourth study found a decrease in the axial diffusivity within the cingulum, inferior longitudinal fasciculus, and inferior frontoccipital fasciculus. CONCLUSIONS: Our review concludes that BPD is associated with measurable WM pathology. Methods such as DTI might emerge as useful tools in the management of BPD. More controlled studies are needed to validate our conclusions.

The effects of yoga on depression and motor function in patients with Parkinson's disease: A review of controlled studies.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative/neuropsychiatric disorder characterized by both motor and non-motor symptomology. The reported prevalence of depression in patients with PD is difficult to ascertain due to overlapping somatic symptoms and failure to self-report symptoms. Although antidepressants remain a first-line treatment, they can have adverse effects. Recently, literature has demonstrated that due to its anti-inflammatory properties, yoga may be an effective nonpharmacologic therapy for depression. METHODS: A search was conducted to identify randomized controlled trials (RCTs) published from January 2000 to January 2019 that assessed the effects of yoga on depression and motor functioning in PD. RESULTS: Three studies met the criteria for inclusion. In one RCT, biweekly yoga resulted in a decrease in depression score (P = .056). In another RCT, weekly yoga resulted in a significant decrease in depression and demonstrated that its therapeutic effects are long-lasting. Finally, in a third RCT, no significant difference was found between control and experimental groups in depression after biweekly yoga. However, yoga was found to be protective against worsening of depression. CONCLUSIONS: Our review suggests that the practice of yoga may be a useful nonpharmacologic adjunctive treatment for depression in patients with PD. However, more controlled RCTs are needed to validate our conclusions.

A systematic review of diffusion tensor imaging studies in drug-naïve OCD patients before and after pharmacotherapy.

BACKGROUND: Obsessive-compulsive disorder (OCD) is difficult to treat. Studies have shown associations of white matter pathology in OCD, as well as various other psychiatric illnesses, using diffusion tensor imaging (DTI). We conducted a systematic review of controlled studies on drugnaïve patients with OCD vs pharmacologically treated patients with OCD to examine whether pharmacotherapy exerts changes on white matter in OCD. METHODS: A search was conducted to identify controlled trials published from January 2010 to July 2018. All studies used DTI to assess for white matter volume in drug-naïve patients with OCD, pharmacologically treated patients with OCD, and healthy controls. RESULTS: Three studies met the criteria for inclusion. The findings of one study suggest that selective serotonin reuptake inhibitors do exert some changes on white matter, some of which appear to reverse abnormalities noted in the fronto-striato-thalamo-cortical pathways. In another study, no differences in white matter parameters were found between drug-naïve patients vs healthy controls. In a third study, high fractional anisotropy in the splenium correlated with a greater severity of OCD. CONCLUSIONS: Our systematic review suggests mixed results regarding whether drug-naïve patients with OCD have a difference in white matter compared with pharmacologically treated patients with OCD, and whether patients with OCD have a difference in white matter compared with healthy controls.

Changes in inflammatory biomarkers before and after SSRI therapy in PTSD: A review.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are regarded as the standard pharmacotherapy for the treatment of posttraumatic stress disorder (PTSD). Recent studies indicate that neuroinflammation is associated with PTSD. We conducted a search of the literature to determine if SSRI efficacy is associated with a decrease in inflammation levels. METHODS: A literature search was conducted to identify studies published from January 2000 to January 2019 that measured changes in inflammatory biomarkers before and after SSRI treatment in patients with PTSD. RESULTS: Four studies met the criteria for inclusion. In one study, SSRI use significantly reduced interleukein-1beta. An open trial of paroxetine found a significant decline in cortisol. In a third study, paroxetine treatment in patients with PTSD and depression showed no significant changes in cortisol. Finally, analysis of cerebrospinal fluid in patients with PTSD showed no significant changes in corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, or insulin-like growth factor 1. Substance P was found to be decreased. CONCLUSIONS: Our review had mixed results regarding whether SSRI therapy for PTSD is associated with a reduction in inflammation. These findings may be due to the heterogeneity of PTSD. More randomized controlled trials are needed due to the potential benefits of SSRIs for reducing inflammation in patients with PTSD (as has been reported in depression studies).

Low high-density lipoprotein and psychopathology: A review.

BACKGROUND: An association between the level of total cholesterol and psychopathology has been the focus of numerous studies. Low total cholesterol has been found to be related to depression, personality disorders, and dissociative disorder. High cholesterol has been associated with schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, generalized anxiety disorder, and posttraumatic stress disorder. However, no reviews of the psychiatric correlates of high-density lipoprotein (HDL) have been published. We reviewed the literature for studies reporting a significant association between low or high levels of HDL and psychopathology. METHODS: A search of major databases (PubMed and CINAHL) was conducted using the following keywords: HDL, depression, anxiety, schizophrenia, OCD, and psychiatric disorders. RESULTS: Eight studies met our search criteria. Six of the 8 studies reported significantly higher rates of depression, anxiety, suicide attempts, and violent behaviors in participants with low HDL. CONCLUSIONS: Overall, a low HDL may not only be associated with risk for cardiac disease, but also with increased risk for serious psychiatric disorders. Further controlled studies are warranted.