Recent studies on the epidemiology of obsessive-compulsive disorder (OCD) estimate 50 million patients suffer from OCD worldwide, thus making it a global problem. The treatment of OCD has changed substantially over the last 2 decades following the introduction of selective serotonin reuptake inhibitors, which provide symptom improvement in ~60% of patients. However, some patients remain resistant to the standard pharmacologic and behavioral treatments. Although some treatment-resistant patients respond to pharmacologic augmentations, others do not, and there is evidence that some of the most severe cases benefit from treatment with neurosurgical interventions. Besides pharmacologic, behavioral, and neurosurgical approaches, different brain stimulation methods—transcranial magnetic stimulation, deep brain stimulation, and electroconvulsive therapy—have been investigated in treatment-resistant patients with OCD. However, available data about the use of these techniques in OCD treatment are quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures. In addition, none of the mentioned treatments have received Food and Drug Administration approval for the treatment of OCD. Nevertheless, promising findings regarding efficacy, tolerability, and non-invasiveness and/or reversibility of these techniques have increased interest in investigating their use in treatment-resistant OCD.

Although addictive syndromes have been traditionally related to substance-use disorders, during the last few decades a novel addictive group, including the so-called “behavioral or no-drug addictions,” has been recognized and has attracted increasing attention for its relevant social impact. This group includes pathological gambling, compulsive shopping, TV/Internet/social network/videogame addictions, workaholism, sex and relationship addictions, orthorexia, and overtraining syndrome. Substance and behavioral addictions show similar phenomenological features, such as craving, dependence, tolerance, and abstinence, and perhaps they share a common possible pathophysiology. It is, however, controversial whether all or at least some of them should be considered real disorders or just normal, albeit extreme, behaviors. The aim of this article is to review current data on pharmacological treatment of behavioral addictions. As no specific and validated treatment algorithms are currently available, only an improved knowledge on their psychopathological, clinical, and neurobiological features may have relevant implications for more focused preventive and therapeutic strategies.

Chronic pain syndromes are often treatment refractory and pose an enormous burden of suffering for the individual. Chronic pelvic pain (CPP) is generally defined as noncyclic pain of at least 6 months duration and severe enough to require medical care or cause disability. CPP has been estimated to have a prevalence of 15% among women of reproductive age. Women are at increased risk for both major depression and chronic pain syndromes such as CPP, and are more likely to report antecedent stressful events, have higher rates of physical and sexual abuse, and subsequently develop posttraumatic stress disorder. High rates of sexual and physical abuse and other trauma have been shown among women with CPP, including symptoms of dyspareunia (pain during intercourse), dysmenorrhea (pain during menstruation), and vulvar pain. A detailed and comprehensive evaluation of the patient with CPP should include a thorough gynecologic exam and a full mental health assessment. Treatment of CPP must include an integrated approach targeted at both the psychiatric comorbidity and pain symptoms. A multidisciplinary treatment team offers the best chance for success with CPP, and it is critical to suggest psychiatric treatment (psychopharmacology and/or psychotherapy) in addition to traditional medical and surgical approaches.

To integrate scholastic literature regarding the prevalence and characteristics of the psychological consequences faced by survivors of the 2011 Fukushima earthquake/tsunami/nuclear disaster, we conducted a systematic review of survivor studies concerning the Fukushima disaster. In August 2019, four literature databases (PubMed, PsycINFO, Psychology and Behavioral Sciences Collection, and ICHUSHI) were used in the literature search. Peer-reviewed manuscripts reporting psychological consequences, either in English or Japanese, were selected. A total of 79 studies were selected for the review. Twenty-four studies (30.4%) were conducted as part of the Fukushima Health Management Survey—large-scale cohort study recruiting the residents of the entire Fukushima prefecture. Study outcomes were primarily nonspecific psychological distress, depressive symptoms, post-traumatic stress symptoms, and anxiety symptoms. The rates of high-risk individuals determined by the studies varied significantly owing to methodological differences. Nevertheless, these rates were mostly high (nonspecific psychological distress, 8.3%-65.1%; depressive symptoms, 12%-52.0%; and post-traumatic stress symptoms, 10.5%-62.6%). Many studies focused on vulnerable populations such as children, mothers of young children, evacuees, and nuclear power plant workers. However, few studies reported on the intervention methods used or their effect on the survivors. As a conclusion, high rates of individuals with psychological conditions, as well as a wide range of mental conditions, were reported among the Fukushima nuclear disaster survivors in the first 8 years after the disaster. These findings demonstrate the substantial impact of this compound disaster, especially in the context of a nuclear catastrophe.

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.

Functional neurological disorder (FND) encompasses a complex and heterogeneous group of neuropsychiatric syndromes commonly encountered in clinical practice. Patients with FND may present with a myriad of neurological symptoms and frequently have comorbid medical, neurological, and psychiatric disorders. Over the past decade, important advances have been made in understanding the pathophysiology of FND within a biopsychosocial framework. Many challenges remain in addressing the stigma associated with this diagnosis, refining diagnostic criteria, and providing access to evidence-based treatments. This paper outlines FND treatment approaches, emphasizing the importance of respectful communication and comprehensive explanation of the diagnosis to patients, as critical first step to enhance engagement, adherence, self-agency, and treatment outcomes. We then focus on a brief review of evidence-based treatments for psychogenic non-epileptic seizures and functional movement disorder, a guide for designing future treatment trials for FND, and a proposal for a treatment research agenda, in order to aid in advancing the field to develop and implement treatments for patients with FND.

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.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.

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.

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.

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the “Metabolic Syndrome of Obesity,” or “Syndrome X,” are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.

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.

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

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.

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.

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.

Our spirits may be regulated by the methylation of our genes. Methylation, acetylation, and other biochemical processes are the molecular switches for turning genes on and off. There is evidence now that certain behaviors, feelings, and psychiatric symptoms may be modified by turning various genes on or off. If classical genetics is the sequence of DNA that is inherited, then epigenetics is a parallel process determining whether a given gene (ie, a sequence of DNA coding for transcription) is expressed into its RNA or is silenced. Epigenetics is now entering psychiatry with the hypothesis that normal genes as well as risk genes can both contribute to a mental disorder. That is, it has long been hypothesized that when “abnormal” genes with an altered sequence of DNA are inherited as risk genes for a mental illness, these risk genes will make an abnormal gene product in neurons, contributing to inefficient information processing in various brain circuits and creating risk for developing a symptom of a mental illness. Now comes the role of epigenetic actions in mental illnesses.