Vortioxetine is an antidepressant with multiple pharmacologic modes of action that enhance release of dopamine, norepinephrine, acetylcholine, and histamine.

Both elevated cardiovascular mortality and low cardiovagal (parasympathetic) heart rate variability (HRV)—a risk factor for postmyocardial infarction—are reported in schizophrenia (SZ). Since a number of medications have strong effects of cardiac conductivity, we thought it important to examine if typical neuroleptic medications might also affect HRV. We examined cardiac vagal activity during both neuroleptic treatment and a drug-free condition in seven SZ patients who were participating in a pilot double-blind, crossover study of placebo and haloperidol treatment. Twenty-four–hour Holter electrocardiograms were analyzed for high frequency HRV, quantitated as the percent of successive normal interbeat intervals greater than 50 milliseconds (PNN50), which is a good index of parasympathetic cardiac modulation. The patients showed unchanged PNN50 (8.4±9.5 versus 8.3±10.5; t=.22, df=6, P=.5) between the haloperidol treatment and drug-free conditions. Despite the elapsed time, change in medication, and altered clinical state, the PNN50s were highly correlated (Spearman r=.98, P=.000). SAPS positive symptom scores declined with treatment from 12.8±6.5 to 8.5±3.5; paired t=3.26: df=6; P=.01. PNN50s were significantly associated with positive (r=-.86, df=6, P=.012) and negative symptom scores (r=-.87, df=6, P=.01). We found low cardiovagal modulation in medication-free SZ patients that was associated with core SZ symptoms and was unchanged by haloperidol and benztropine treatment. The reduced HRV in SZ patients at baseline may render them at greater cardiovascular risk than healthy subjects when treated with medications having strong cardiovascular effects.

Research advances have led to three methods for selectively activating one half of the autonomic nervous system in humans.The first method is an ancient yogic technique called unilateral forced nostril breathing (UFNB) that employs forced breathing through only one nostril while closing off the other. The second method works by stimulation of an autonomic reflex point on the fifth intercostal space near the axilla. The most recent method employs unilateral vagus nerve stimulation (VNS) via the mid-inferior cervical branch and requires surgical implantation of a wire and pacemaker. UFNB is non-invasive and seems to selectively activate the ipsilateral branch of the sympathetic nervous system with a possible compensation effect leading to contralateral VNS. UFNB and VNS have been employed to treat psychiatric disorders. While UFNB has been studied for its potential effects on the endogenous ultradian rhythms of the autonomic and central nervous system, and their tightly coupled correlates, VNS has yet to be studied in this regard. This article reviews these three methods and discusses their similarities, putative mechanisms, their studied effects on the endogenous autonomic nervous system and central nervous system rhythms, and their implications for the treatment of psychiatric disorders.

Recognition and treatment of schizophrenia has largely focused on positive symptoms of the disorder, such as delusions, hallucinations, and disorganization. However, other important symptoms, such as depression, cognition, and social functioning, have not received comparable attention. Fifty percent of schizophrenic patients suffer from comorbid depression, which is a major risk factor for suicide in this population, while 10% to 25% suffer from comorbid obsessive-compulsive disorder. Cognitive deficits commonly observed in patients with schizophrenia include problems with concentration, attention, and memory, as well as problem-solving and verbal skills. These deficits are observed at early stages of the illness and can predict deficits in functional capabilities, such as occupational and social skills, educational attainment, and the ability to live independently. The severity of such impairments affects all patients in this population, including up to 10% of patients working full time and up to one third of those working part time. In light of the debilitating effects of depression, cognitive impairment, and other aspects of affective functioning on the quality of life of patients with schizophrenia, physicians need to partner with their patients to address these concerns and determine an appropriate treatment regimen. This can be done with simple functional-based cognitive questioning, the use of evidence-based psychosocial practices, and psychoeducation on the many pharmacotherapeutic options. It is recommended that depressive or suicidal symptoms of schizophrenia be treated with an antidepressant or mood stabilizer only if the symptoms have not subsided after treatment of the psychosis with an atypical antipsychotic. Additionally, relative to older medications, atypicals have demonstrated benefit in improving some of the cognitive impairments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in social interactions and perseverative and stereotypical behavior. Growing evidence points toward a critical role for synaptic dysfunction in the onset of ASD, and synaptic function is influenced by glial cells. Considering the evidence that neuroinflammation in ASD is mediated by glial cells, one hypothesis is that reactive glial cells, under inflammatory conditions, contribute to the loss of synaptic functions and trigger ASD. Ongoing pharmacological treatments for ASD, including oxytocin, vitamin D, sulforaphane, and resveratrol, are promising and are shown to lead to improvements in behavioral performance in ASD. More importantly, their pharmacological mechanisms are closely related to anti-inflammation and synaptic protection. We focus this review on the hypothesis that synaptic dysfunction caused by reactive glial cells would lead to ASD, and discuss the potentials of antineuroinflammatory therapy for ASD.

Background: Clinical trials of aripiprazole, a recentl Food and Drug Administration-approved atypical antipsychotic, included elderly patients, but more data are needed on the effects of aripiprazole in this population, especially those with comorbid medical illnesses.

Objective: To assess the response and safety of aripiprazole treatment in elderly patients with phrenia or schizoaffective disorder.

Method: Data was obtained by retrospective review of medical records. Aripiprazole was used to treat 10 elderly hospitalized patients between 62 and 85 years of age who manifested signs of psychosis related to schizophrenia or schizoaffective disorder. All patients had been treated previously with atypical and classic antipsychotics. Response was assessed by clinical observation of patients' behavior and Clinical Global Impression Scale assigned retrospectively.

Results: Seven patients responded to treatment, two did not respond, and one had a partial response. The mean Clinical Global Impression Scale scores improved from 6 (severely ill) at baseline to 2.3 (much improved) at discharge. Treatment was discontinued in the two patients who did not respond. Of the seven patients who responded, four presented with positive symptoms and showed significant improvement while three presented with positive and negative symptoms and both symptoms improved significantly. Four patients had preexisting extrapyramidal symptoms (EPS) and these symptoms decreased in three patients. In addition, two patients were able to discontinue antiparkinson medications. One patient who had severe tardive dyskinesia showed significant improvement in the dyskinetic symptoms. Four patients showed postural hypotension (without clinical symptoms) which resolved over time without treatment. Six patients showed a mean weight loss of 5.2 lbs. No adverse consequences occurred when divalproex sodium, carbamazepine, clonazepam or citalopram were given concurrently.

Conclusion: The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, weight gain, anticholinergic effects, and QTc prolongation gives preliminary indication that aripiprazole may be a safe and effective medication for elderly patients with schizophrenia or schizoaffective disorder.

Current measures for major depressive disorder focus primarily on the assessment of depressive symptoms, while often omitting other common features. However, the presence of comorbid features in the anxiety spectrum influences outcome and may effect treatment. More comprehensive measures of depression are needed that include the assessment of symptoms in the anxiety–depression spectrum. This study examines the reliability and validity of the Symptoms of Depression Questionnaire (SDQ), which assesses irritability, anger attacks, and anxiety symptoms together with the commonly considered symptoms of depression. Analysis of the factor structure of the SDQ identified 5 subscales, including one in the anxiety–depression spectrum, with adequate internal consistency and concurrent validity. The SDQ may be a valuable new tool to better characterize depression and identify and administer more targeted interventions.

Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% Cl 0.01 to 0.36).The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest.

Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.

Bipolar disorder with co-occurring attention-deficit/hyperactivity disorder (ADHD) is a challenge to treat. Ten previous reports have shown potential benefit of a micronutrient treatment (consisting mainly of vitamins and minerals) for various psychiatric symptoms, including mood and ADHD. This case study aimed to investigate the longer term impact of the micronutrients on both psychiatric and neurocognitive functioning in an off-on-off-on (ABAB) design with 1 year follow-up. A 21-year-old female with bipolar II disorder, ADHD, social anxiety, and panic disorder entered an open-label trial using a nutritional treatment following a documented 8 year history of ongoing psychiatric symptoms not well managed by medications. After 8 weeks on the formula she showed significant improvements in mood, anxiety, and hyperactivity/impulsivity. Blood test results remained normal after 8 weeks on the formula. She did not report any adverse side effects associated with the treatment. She then chose to come off the formula; after 8 weeks her depression scores returned to baseline, and anxiety and ADHD symptoms worsened. The formula was reintroduced, showing gradual improvement in all psychiatric symptoms. This case represents a naturalistic ABAB design showing on-off control of symptoms. After 1 year, the patient is now in remission from all mental illness. Neurocognitive changes mirrored behavioral changes, showing improved processing speed, consistency in response speed, and verbal memory. A placebo response and expectancy effects cannot be ruled out although previous poor response to treatment and the duration of the current positive response decrease the likelihood that other factors better explain change. These consistently positive outcomes alongside an absence of side effects indicate that further research, particularly larger and more controlled trials, is warranted using this multinutrient approach.

While impairments in cognitive emotional processing are key to the experience of mood disorders, little is understood of their shared and distinct features across major depressive disorder (MDD) and bipolar disorder (BD). In this review, we discuss the similarities and differences in abnormal emotional processing associated with mood disorders across the cognitive domains of perception, attention, memory, and reward processing, with a particular focus on how these impairments relate to the clinical profile of the disorders. We consider behavioral and neuroimaging evidence, especially that of the growing consensus surrounding mood-congruent biases in cognition, in combination with state- and trait-related characteristics in an attempt to provide a more comprehensive and translational overview of mood disorders. Special consideration is given to the shared phenomenon of mood instability and its role as a potential transdiagnostic marker across the prodrome and maintenance of mood disorders.

Along with the development of selective sertonin reuptake inhibitors there has been a tremendous widening of the definition of depression and an impressive decrease in the placebodrug difference in controlled studies. In the early 1960s, about one third of depressed patients improved with placebo and two thirds with active compounds. Current controlled studies suggest that the situation has certainly not improved. The Sequenced Treatment Alternatives to Relieve Depression Study found that response rates to new compounds after the failure of the first antidepressant are low. The monoamine hypothesis of depression was formulated in the mid 1960s based on the antidepressant efficacy of the monoamine reuptake inhibitors, monoamine oxidase inhibitors, and the depressogenic effects of reserpine as a monoamine depleter. However, no monoamine-related finding has been found that is diagnostic for depression. A second major hypothesis regarding depression has been the stress cortisol hypothesis. However, blood cortisol levels are not diagnostic of depression. Psychiatric clinicians are convinced that there are patients for whom antidepressants have made the difference between life and death. However, physicians may generalize unjustifiably based on single dramatic cases to a much larger diagnostic group. Perhaps there are many causes of different types of human sadness, and perhaps only some of these involve mechanisms related to monoamines. Thus, perhaps only some kinds of depression are responsive to monoamine affecting antidepressants.

Despite emerging evidence that distress and adversity can contribute to negative health outcomes in cancer, little is known about the brain networks, regions, or circuits that can contribute to individual differences in affect/distress states and health outcomes in treated cancer patients. To understand the state-of-the-science in this regard, we reviewed neuroimaging studies with cancer patients that examined the associations between negative affect (distress) and changes in the metabolism or structure of brain regions. Cancer patients showed changes in function and/or structure of key brain regions such as the prefrontal cortex, thalamus, amygdala, hippocampus, cingulate cortex (mainly subgenual area), hypothalamus, basal ganglia (striatum and caudate), and insula, which are associated with greater anxiety, depression, posttraumatic stress disorder (PTSD) symptoms, and distress. These results provide insights for understanding the effects of these psychological and emotional factors on peripheral stress-related biobehavioral pathways known to contribute to cancer progression and long-term health outcomes. This line of work provides leads for understanding the brain-mediated mechanisms that may explain the health effects of psychosocial interventions in cancer patients and survivors. A multilevel and integrated model for distress management intervention effects on psychological adaptation, biobehavioral processes, cancer pathogenesis, and clinical outcomes is proposed for future research.

Is human immunodeficiency virus still a terminal condition? Recent advances in treatment have significantly reduced both mortality and morbidity associated with HIV, but these treatments have not been successful in eradicating the virus itself. As such, HIV has evolved into a chronic condition that is complicated by neurocognitive factors. Cognitive difficulties associated with HIV are characterized by a subcortical pattern with primary deficits in information processing speed and psychomotor speed. These deficits interfere with the ability of patients to complete important instrumental activities of daily living even in the absence of dementia. Treatment of HIV improves neurocognitive functioning, but the regimens are complex and patient adherence is critical. Cognitive factors can negatively impact treatment adherence, which in turn results in poorer immunological, cognitive, and psychiatric outcome. This cycle emphasizes the important interrelationships between symptom expression and treatment outcome in patients with HIV. The nature of these relationships will change with further developments in treatment regimens such as once-daily dosing. Less complex treatment approaches should improve health outcome as well as provide additional opportunities to further understand the impact of HIV on brain function.

It is essential to recognize and treat psychosis in Parkinson's disease for several reasons. Studies have shown that psychosis in Parkinson's disease patients is a strong risk factor for nursing home placement. Psychosis may be the greatest source of stress for caretakers of Parkinson's patients; it is often persistent, and its presence markedly increases mortality. Treatment of psychotic symptoms should occur only after potential medical and environmental causes of delirium have been eliminated or addressed. Initial pharmacologic changes should include limiting the patient's antiparkinsonian medications to those that are necessary to preserve motor function. Should that fail, an atypical antipsychotic is presently the treatment of choice. An emerging treatment option is acetylcholinesterase inhibitors. This article reviews what is currently known about the course, prognosis, and treatment strategies in Parkinson's disease psychosis.

Almost 36 million people will have dementia in 2010—an alarming figure set to double every 20 years with the “greying” of the world population. Alzheimer's disease (AD) and dementia have enormous financial and social impacts on society. Prevention or illness delay of even a small percentage of cases would provide significant cost benefits for health-care systems. This review considers the rationale for a combined B-vitamin and antioxidant supplement (Cerefolin NAC) in treating and slowing AD-related cognitive decline.

Vitamin B12 and folate deficiencies are associated with various cognitive disorders, including dementia. In the 1980s, plasma total homocysteine (tHcy) assays were introduced to assist in diagnosing these deficiencies. Hey is derived from dietary methionine. Cells re-methylate Hey to methionine using B12-dependent methionine synthase; 5-methyltetrahydrofolate (5-MTHF) acts as a methyl donor (Figure 1A). Alternatively, Hey is converted to cystathionine, and ultimately cysteine, by B6-dependent cystathionine β-synthase. Blood Hey levels rise in B6, B6, and folate deficiencies.Higher levels are also associated with aging, smoking, male gender, renal impairment, and drugs including methotrexate, metformin, and levodopa.

Using tHcy as a marker, B vitamin deficiencies were found to be highly prevalent in the elderly. This led to speculation that elevated blood Hey, hyperhomocysteinemia, might occur commonly in dementias, including AD. Hyperhomocysteinemia implies impaired meth-ylation reactions (hypomethylation), with predictable adverse effects for neurotransmitter synthesis and AD neuropathology. Hey is also associated with vascular disease, itself a risk factor for dementia.

Evidence for the “homocysteine hypothesis of dementia” came with reports of hyperhomocysteinemia in patients with clinically and pathologically confirmed AD. Raised blood levels were also observed in mild cognitive impairment (MCI) and vascular dementia. Although elevated Hey could be a consequence of, or coincidental with, dementia hyperhomocysteinemia, it is now recognised to be associated with an increased risk for both cognitive decline and incident dementia.