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Accidental falls and major depressive disorder (MDD) are two common conditions associated with aging. Initial treatment of MDD often starts with administering antidepressants, followed by transcranial magnetic stimulation (TMS) for treatment-resistant individuals. The purpose of this case study was to determine the effect of repetitive TMS (rTMS) on postural control of an individual with MDD. A 44-year-old male with recurrent severe MDD was assessed for postural balance during eyes closed and eyes open conditions, pre and post three consecutive sessions receiving high-frequency rTMS (NeuroStar). Total excursion and velocity of sway significantly decreased following rTMS treatment when eyes were closed (p

Background: Schizophrenia-like presentations of frontotemporal dementia (FTD) are well documented in medical literature, especially during the initial stage of the illness. We present an interesting case of middle-aged white male, who was initially misdiagnosed with major depression at age 50 and then with schizophrenia due to florid psychosis typically seen in Mild Behavioral Impairment (MBI). It was not until over 4-years that a detailed clinical history along with specific investigations confirmed the diagnosis of right temporal variant frontotemporal dementia (rtv-FTD). Methods: The unusual presentation of this case warranted 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography (FDG-PET) and comprehensive neuropsychological testing to estblish a final diagnosis. Results: The results from neuroimaging and neuropsychological testing supported a diagnosis of rtv-FTD without any evidence for Alzheimer’s dementia. Conclusion: This case illustrates that late-onset atypical psychiatric symptoms should be evaluated for neurocognitive disorders, and the evaluation should include neuroimaging. It is preferable that the neuroimaging findings be personally interpreted by the provider, who therefore needs to be skilled in interpreting neuroimaging studies.

Objective To demonstrate how effectively aripiprazole can be utilized to manage antipsychotic-induced hyperprolactinemia. Methods The files of 3 female patients with a history of psychotic illness and hyperprolactinemia who were treated at a state hospital between February 2018 and May 2019 were retrospectively analyzed. All were found to have elevated prolactin levels and underwent treatment with aripiprazole in addition to their concomitant medications. Results In general, the addition of aripiprazole to the treatment regimen of each of the patients corresponded to a decline in their serum prolactin levels. Conclusions Hyperprolactinemia is frequently observed in patients treated with antipsychotic medications. Low-dose treatment with aripiprazole may offer a relatively rapid relief from sustained hyperprolactinemia and associated adverse effects even after a long-acting injectable is discontinued.

Clozapine is the only approved treatment for Treatment-Refractory Schizophrenia. Here we describe a case series of three hospitalized patients with clozapine nonresponse. One of them responded to clozapine after dose adjustments were made for an interaction between clozapine and ciprofloxacin. The other two cases remained clozapine nonresponders despite optimizing clozapine treatment. However, both these patients responded to other antipsychotic medications (APMs) with better tolerability than observed with clozapine treatment. This case series focuses on diagnosing a genuine from a pseudo-nonresponse to clozapine and to consider other APMs in genuine nonresponse before switching to invasive interventions, such as ECT.

Background Treatment-resistant aggressive behavior is a complex psychoneurological phenomenon with high health care and societal costs commonly observed in mental illnesses involving psychosis. Here, we report a preliminary evaluation of treatment with dextromethorphan/quinidine in 4 adult patients with significant history of psychosis-related aggression and impulsive behaviors. Methods The files of 4 inpatients with DSM-5-defined psychotic disorder and treatment-resistant aggression treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were retrospectively analyzed. The patients (age: mean ± SD = 59.8 ± 7.6) received open-label treatment with dextromethorphan/quinidine (final dose 20 mg/10 mg twice daily) for at least 12 weeks. Outcome was measured on the basis of patient self-report, treatment team evaluation, and physical examination by psychiatrists and primary care physicians. Results Three of the 4 patients were considered responders to dextromethorphan/quinidine based on clinical impressions of reduction in aggression and impulsive behavior. The nonresponder, who had a history of multiple traumatic brain injuries, showed mild improvement in agitation but continued to display impulsive self-harm behavior despite treatment. Dextromethorphan/quinidine was generally well-tolerated. No metabolic, gastrointestinal, or cardiovascular side effects were observed. Conclusions These preliminary findings support dextromethorphan/quinidine as a potential alternative to conventional regimens for treating aggression and impulsive behavior in patients with psychotic disorder. These results should be interpreted cautiously, as extended, double-blinded, placebo-controlled studies with a larger sample size are needed to validate findings from this retrospective case series.

In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing's syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=−0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.

Accurate and noninvasive quantification of regional cerebral blood perfusion (CBF) of the human brain tissue would advance the study of the complex interplay between human brain structure and function, in both health and disease. Despite the plethora of works on CBF in gray matter, a detailed quantitative white matter perfusion atlas has not been presented on healthy adults using the International Consortium for Brain Mapping atlases. In this study, we present a host of assurance measures such as temporal stability, spatial heterogeneity and age effects of regional and global CBF in selected deep, cortical gray matter and white matter tracts identified and quantified using diffusion tensor imaging (DTI). We utilized whole brain high-resolution DTI combined with arterial spin labeling to quantify regional CBF on 15 healthy adults aged 23.2-57.1years. We present total brain and regional CBF, corresponding volume, mean diffusivity and fractional anisotropy spatial heterogeneity, and dependence on age as additional quality assurance measures to compare with published trends using both MRI and nuclear medicine methods. Total CBF showed a steady decrease with age in gray matter (r=-0.58; P=.03), whereas total CBF of white matter did not significantly change with age (r=0.11; P=.7). This quantitative report offers a preliminary baseline of CBF, volume and DTI measurements for the design of future multicenter and clinical studies utilizing noninvasive perfusion and DT-MRI.

Despite advances in pharmacotherapy, schizophrenia continues to carry a high societal disease burden related to positive and negative symptoms, and neurocognitive deficits and severe functional impairment. Findings from epigenetics have yet to translate the epigenetics targets to efficacious drug therapy. We review the repertoire of CNS pharmacology of curcumin derived from Curcuma Longa, commonly known as “turmeric”: the well-known curry extract. We highlight the body of evidence in support of the emerging role of curcumin as a panhistone deacetylase (HDAC) inhibitor regulating the expression of genes involved in inflammation and NMDA N-methyl-aspartic acid (NMDA)-glutamate systems, as related to schizophrenia. Based on the findings from translational studies of curcumin extracts, curcumin C-3 complex formulation (Supercurcumin™) and patented liposome-based curcumin (Lipocurc™), we propose that intravenous infusion of Lipocurc™ holds promise as the novel drug lead and preferred targeted brain delivery mode in reprogramming faculty epigenetics network and in remodeling restrictive chromatin configuration in schizophrenia. Phase II/Phase III epigenetics-biomarker-based randomized placebo-controlled trials in treatment resistant schizophrenia are warranted. Our approach of intravenous infusion of Lipocurc™ behaving as pan HDAC inhibitor represents a new paradigm of drug development in combining targeting epigenetics footprints with brain-specific drug delivery system in schizophrenia. Lipocurc™ can open the Pandora box in unexplored therapeutics vistas in modifying the phenotype of treatment resistant schizophrenia.

Self-awareness (SA) is a cognitive ability to differentiate between self and non-self cues and is pivotal to understand the behavior of other human beings. For this reason, there has been a significant interest to investigate the neurobiology of SA in human subjects. So far the majority of such research has been conducted in healthy subjects but a significant relationship between impaired SA and poor psychosocial outcome in schizophrenia has stimulated neuroimaging research in this patient population. The results from small number of neuroimaging studies in schizophrenia suggest that impaired SA may be mediated by a dysfunction of cortical midline structures. This paper is an attempt to review emerging functional magnetic resonance imaging (fMRI) data in schizophrenia and to propose a hypothetical model of deficits in SA in schizophrenia that can be tested in future research. The model is refined from the available literature and proposes that self-referential activity appears to reflect a shift from activation of anterior to posterior cortical midline structures in schizophrenia subjects, which may be related to lack of functional connectivity between different cortical midline regions.

The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post-hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high-risk behavior (defined as low-probability/high magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents.

Post-traumatic stress disorder (PTSD) is increasingly recognized as a serious and potentially debilitating condition in combat veterans returning from Iraq and Afghanistan. Exposure to a potentially life-threatening event such as military combat may be followed by PTSD. Despite recent advances in pharmacotherapy for PTSD, monotherapy with the currently available medications is only partially effective, as demonstrated in large clinical trials of combat veterans with PTSD. This underscores the need to investigate novel combination strategies to enhance treatment response in PTSD. The α-1 adrenergic receptor (AR) antagonist, prazosin, appears promising in recent studies for its capacity to reduce trauma-related nightmares (a group B night-time intrusion symptom) and insomnia (a group D night-time arousal symptom), while recent evidence supports using the β-AR antagonist, propranolol, to dampen the emotional content of traumatic memories (daytime intrusion symptoms including flashbacks, intrusive recollections of traumatic event, and heightened physiological reactivity/ responsivity to trauma reminders). In this review, we present data supporting the potential utility of combined drug regimen (prazosin and propranolol) acting through different noradrenergic mechanisms, with the potential to target more than one set of PTSD symptoms to optimize PTSD treatment.

In addition to changes in declarative memory and the hippocampus, corticosteroid excess is associated with prefrontal cortex changes. We previously reported that patients receiving exogenous corticosteroid therapy had impaired performance on prefrontal cortex-related tasks, including working memory and executive functioning tasks. Glutamate release inhibitors attenuate corticosteroid-effects on the hippocampus in both animal and human models. Twenty-eight outpatients receiving chronic prednisone therapy for transplant rejection or other medical conditions were randomized to lamotrigine (a glutamate release inhibitor) or placebo for 24 weeks. Dorsolateral prefrontal cortex (DLPFC) volume was manually traced from MRI scans by trained staff members. Cognition was examined using the Stroop Color Word Test (SCWT), Delis-Kaplan Executive Function System (D-KEFS) and the Trail Making Test. Groups were compared using analysis of covariance. Consistent with prior findings in corticosteroid-treated patients, baseline cognitive function was in the low normal range. At baseline, prednisone duration showed a trend towards negative correlation with SCWT and D-KEFS inhibition switching time error scores, and DLPFC volume showed a trend towards a positive correlation with SCWT scores. No significant between-group differences in outcomes were observed following lamotrigine therapy. Thus, this study found lamotrigine to not be associated with either positive or negative effects on cognition or DLPFC volume. Copyright © 2010 John Wiley & Sons, Ltd.

Background Smaller hippocampal volume has been reported in some adult and pediatric studies of unipolar major depressive disorder. It is not clear whether the smaller hippocampal volume precedes or is a consequence of the illness. Early-life adversity is associated with both smaller hippocampal volume and increased vulnerability to depressive disorder. Hippocampal changes may mediate the relationship between early-life adversity and depressive illness in a subset of patients. However, there are no reports of longitudinal clinical studies that have examined this issue. Methods Thirty adolescents with unipolar major depressive disorder, 22 adolescent volunteers with no personal history of a psychiatric illness including depression but who were at high risk for developing depression by virtue of parental depression (high-risk group), and 35 adolescent volunteers with no personal or family history of a psychiatric disorder (control subjects) underwent volumetric magnetic resonance imaging studies. Information was also gathered on early and recent adverse experiences with standard interviews. The participants were followed for up to 5 years to assess the onset and clinical course of depression. Results Depressed and high-risk groups had significantly smaller left and right hippocampal volumes than control subjects. Higher levels of early-life adversity were associated with smaller hippocampal volumes. Smaller hippocampal volume partially mediated the effect of early-life adversity on depression during longitudinal follow-up. Conclusions Smaller hippocampal volume in adolescents at high risk for depression suggests that it may be a vulnerability marker for the illness. Early-life adversity may interact with genetic vulnerability to induce hippocampal changes, potentially increasing the risk for depressive disorder.

Background: Excessive corticosteroid exposure is associated with atrophic effects on the human hippocampus and amygdala. These effects seem to be, at least in part, mediated through corticosteroid-induced release of glutamate. We previously reported that lamotrigine, a glutamate release inhibitor, significantly improved declarative memory but did not change hippocampal volume, as compared with placebo, in corticosteroid-treated patients. To our knowledge, no data are available on preventing or reversing the impact of corticosteroids on the amygdala. Methods: We examined the effects of 24 weeks of randomized placebo-controlled lamotrigine therapy on amygdala volume and mood in 28 corticosteroid-treated patients (n = 12, placebo; n = 16, lamotrigine). Amygdala volumes were measured from tracings of the magnetic resonance images from weeks 0 and 24. Mood was assessed every 2 weeks with the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Results: An analysis of covariance revealed that patients on lamotrigine had significantly larger left amygdala volume at week 24 than patients on placebo after controlling for baseline volume. Neither exit nor week 24 analysis of covariance of Hamilton Depression Rating Scale and Young Mania Rating Scale revealed a significant difference between lamotrigine and placebo groups. Conclusions: Results suggest that lamotrigine attenuated the effects of corticosteroids on the left amygdala. Larger trials are warranted to confirm these findings.

Impaired insight into illness is commonly observed across various psychiatric illnesses, but is most frequent in patients with schizophrenia. The clinical relevance and public health impact of poor insight is reflected by its close association with important clinical outcome measures, such as treatment non-adherence, lower psychosocial functioning, poor prognosis, involuntary hospitalization, and higher utilization of emergency services. Although the neurobiology of insight has not been determined, data from neurocognitive and a few structural imaging studies provide some understanding of the neurobiological underpinnings of insight function in schizophrenia. Using published and preliminary data, we propose a hypothetical model of insight that may help initiate neurobiological investigations in this complex area.

Insight into illness has been identified as a clinically important phenomenon, in no small part due to an association with treatment-adherence. An increasing number of studies, but not all, have observed poor insight to be a reflection of cognitive dysfunction in schizophrenia. A review of 34 published English-language studies found a significant number (i.e., 21) reporting a relationship between insight deficits and impaired performance on cognitive tasks primarily mediated by frontal cortex. A significant number of reviewed studies examined insight function in more than one psychiatric population, including bipolar and schizoaffective disorder. The most replicated findings from these studies were the correlations between insight deficits and impaired performance on the Wisconsin Card Sorting Test (WCST). More specifically, WCST perseverative errors correlated positively and the number of categories completed correlated negatively with poor insight, suggesting that impaired insight may be mediated by deficiencies in conceptual organization and flexibility in abstract thinking. Since the WCST requires the ability to demonstrate conceptual flexibility through the generation, maintenance and switching of mental sets along with the capacity to use verbal feedback to correct errors, it would appear that such 'executive' functions are most related to insight. In addition, recently identified structural correlates of poor insight in schizophrenia show some association with anosognosia in neurological patients. This review will discuss the implications of these findings and directions for future research.

Deficits in insight are multidimensional, and include symptom unawareness and misattribution. We and others have observed that these deficits may be related to a prefrontal dysfunction. However, few studies have examined the relationship between specific prefrontal sub-regions and the awareness and attributional dimensions of insight in schizophrenia. This study examined the correlation between insight dimensions of awareness and attribution of symptoms and dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) volume in 14 subjects with first-episode, antipsychotic-naïve (FEAN) schizophrenia. In addition, 21 healthy subjects provided control data for volumetric assessments. Insight was assessed with Scale to Assess Unawareness of Mental Disorders. Morphometric assessments were adjusted for intra-cranial volume and were conducted by trained raters blind to clinical information using BRAINS-2. Average scores on current awareness of symptoms (1=aware; 5=unaware) were negatively correlated with right DLPFC volume and average scores on current attribution of symptoms (1=attribute; 5=misattribute) with right medial OFC volume. Unawareness and misattribution of symptoms in FEAN schizophrenia may have distinct neuroanatomical bases. DLPFC deficits may have resulted in illness unawareness by interfering with self-monitoring, while OFC abnormalities may have mediated symptom misattribution by conferring aberrant salience to perceived symptomatology.

The authors examined whether African Americans, compared with whites, received guideline-concordant care for bipolar I disorder.A retrospective analysis was conducted of data for patients who received a diagnosis of bipolar I disorder in fiscal year 2001 and received care in facilities in the Department of Veterans Affairs (VA) mid-Atlantic region. Indicators of guideline-concordant care were based on prescription data and data on utilization of inpatient and outpatient services from VA databases.A total of 2,316 patients with a diagnosis of bipolar I disorder were identified. Their mean age was 52 years; 9.4 percent (N=218) were women, and 13.1 percent (N=303) were African American. Overall, mood stabilizers were prescribed for 74.6 percent (N=1,728) of the patients; 67.1 percent (N=1,554) had an outpatient mental health visit within 90 days after the index diagnosis, and 54.3 percent (N=1,258) had an outpatient visit within 30 days after discharge from a psychiatric hospitalization. Multivariate logistic regression analyses with adjustment for sociodemographic and facility factors revealed that African Americans were less likely than whites to have an outpatient follow-up visit within 90 days after the index diagnosis. Race was not associated with receipt of mood stabilizers or use of outpatient services after a hospital discharge.Although a majority of patients received guideline-concordant care for bipolar disorder, potential gaps in continuity of outpatient care may exist for African-American patients.

Background: Few treatment studies of schizotypal personality disorder (SPD) have investigated the new, atypical antipsychotic drugs. This study examined the efficacy and tolerability of olanzapine, an atypical antipsychotic drug, in a series of patients with DSM-IV diagnosed schizotypal personality disorder. Method: This was a 26-week, open-label study with flexible dose design in 11 subjects with a diagnosis of schizotypal personality disorder based on Structured Clinical Interview for DSM-IV (SCID) and Personality Disorder Examination (PDE Journal of Psychiatric Disorders 1 (1987) 1). Subjects were treated with a low dose (average 9.32 mg/day) of olanzapine. Psychopathology was assessed at baseline and at the end of the study and analyzed with last observation carried forward analysis. Results: Patients showed significant improvements in psychosis and depression ratings, as well as in overall functioning. Olanzapine was well tolerated, though significant weight gain was observed. Conclusion: This study provides preliminary data regarding olanzapine efficacy and tolerability in schizotypal personality disorder subjects. These data need to be confirmed in larger controlled clinical trials.

Objective: Treatment of coexisting medical comorbidities may reduce the risk of adverse outcomes among patients with bipolar disorder. We determined the prevalence of general medical conditions in a population-based sample of patients diagnosed with bipolar disorder in the Veterans Administration (VA). Methods: We conducted a cross-sectional study of patients (n = 4310) diagnosed with bipolar disorder in fiscal year 2001 receiving care at VA facilities located within the mid-Atlantic region. General medical conditions were assessed using ICD-9 codes, and we compared the prevalence of each condition in our bipolar sample with national data on the VA patient population. Results: The mean age was 53 (SD = 13), 10% were women, and 12% African-American. The mean age of the VA national patient population was higher (58 years). The most prevalent conditions among patients with bipolar disorder included cardiovascular (e.g. hypertension, 35%), endocrine (e.g. hyperlipidemia, 23%; diabetes, 17%), and alcohol use disorder (25%). When compared with national data, the prevalence of diabetes was higher in the bipolar cohort than in the national cohort (17.2% versus 15.6%; p = 0.0035). Hepatitis C was more common in the bipolar group than the national cohort (5.9% versus 1.1%; p

Recently with the changing landscape of the aging population and the increase in incidence of Alzheimer’s disease (AD), there has been marked interest to develop strategies to prevent, delay and modify AD. We review the diverse lines of evidence in support of the emerging role of cAMP-mediated Phosphodiesterase (PDE) signalling with respect to aging, inflammation and depression. In view of the link of PDE to Epigenetic complex, targeting PDE through designing modulators and inhibitors of PDE may represent a novel approach in AD therapeutics. We review critically the translational studies of the proprietary Zembrin extract harvested and processed from the South African plant, Sceletium tortuosum, highlighting the dual property of Zembrin in targeting coupling of PDE and serotonin signaling mechanisms in vitro and in vivo models of AD and cognition. The promising clinical findings of Zembrin in cognition suggest that Zembrin extract may merit randomized controlled trials in AD to establish the efficacy and safety in AD.

Converging evidence identifies stress-related disorders as putative risk factors for Alzheimer Disease (AD). This article reviews evidence on the complex interplay of stress, aging, and genes-epigenetics interactions. The recent classification of AD into preclinical, mild cognitive impairment, and AD offers a window for intervention to prevent, delay, or modify the course of AD. Evidence in support of the cognitive effects of epigenetics-diet, and nutraceuticals is reviewed. A proactive epigenetics diet and nutraceuticals program holds promise as potential buffer against the negative impact of aging and stress responses on cognition, and can optimize vascular, metabolic, and brain health in the community.