Recent literature regarding drug-drug, herb-drug, and food-drug interactions must not be ignored; nor can they always be taken at face value. Studies have shown that St. John's wort (SJW) (Hypericum perforatum) can reduce plasma levels of indinavir, cyclosporin, digoxin, and possibly other drugs as well. Current knowledge regarding the metabolism of these medications suggests that the cytochrome P450 (CYP) drug metabolizing enzyme systems cannot account for all these effects. It has been reported that the P-glycoprotein (Pgp) transmembrane pump is also induced by SJW. Medications that are substrates of both CYP 3A4 a Pgp are of particular concern and may pose special interaction risks when combined with certain foods or botanical products such as SJW.

The major neurological complication of human immunodeficiency virus type 1 (HIV-1) infection is cognitive impairment, which can range in severity from a mild subclinical cognitive inefficiency to a severe dementing illness. Mild to moderate cognitive impairment is identified primarily by neuropsychological tests. The prevalence and severity of cognitive impairment associated with HIV-1 infection increases as the disease progresses. Deficits in attention, information processing speed, memory, and motor abilities can occur early in the course of HIV-1 infection, with deficits in abstraction and executive functions observed in later stages of infection. The nature of the cognitive impairment observed is thought to reflect the effects of HIV-1 infection on the integrity of subcortical or frontostriatal brain systems. Issues related to the detection of subclinical to severe cognitive impairment are discussed, along with the clinical significance of mild cognitive impairment as a significant risk factor for mortality in HIV-1 infection. The need to control for possible confounding factors that can influence test performance is also reviewed.

Pseudobulbar affect, thought by many to be a relatively newly described condition, is in fact a very old one, described as early as the 19th century. It refers to those who experience inappropriate affect, disconnected from internal state, or mood, generally thought to be the result of an upper motor neuron injury or illness. One possible explanation for this condition’s relative obscurity is the dearth of treatment options; clinical medicine is not typically in the habit of identifying conditions that cannot be modified. Now, however, there is good evidence for the treatment of pseudobulbar affect, and even a therapy approved for use by the U.S. Food and Drug Administration (FDA). As a result, appropriate identification and subsequent management of pseudobulbar affect is more important than ever. This article purports to summarize the origins of pseudobulbar affect, most current hypotheses as to its physiopathology, clinical identification, and evidence for management.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests in childhood and can persist into adolescence and adulthood. Impairments associated with ADHD can impact quality of life, social interactions, and increase the risk of morbidity and mortality; however, for many patients, effective treatment can lessen these effects. Pharmacotherapy with stimulants or nonstimulants is recommended in conjunction with psychosocial therapy for most patients. Determining the optimal pharmacotherapy can be complex, and the clinician needs to consider many factors such as the patient’s age, comorbidities, and lifestyle. Furthermore, the needs of the patient with ADHD will change over time, with specific challenges to consider at each stage of life. A variety of Food and Drug Administration (FDA)-approved stimulant and nonstimulant formulations are available with different modes of delivery and durations of effect. This armamentarium of ADHD medications can be used to individualize ADHD treatment for each patient’s needs. This article combines current information from the literature and the first-hand experience of the authors to provide guidance on ADHD treatment options for patients of different ages and for some of the more common comorbidities.

Studies on schizophrenia (SZ) have documented an increased presence of cavum septi pellucidi (CSP) in individuals suffering from the illness. Moreover, the presence of CSP has been cited in support of the early neurodevelopmental hypothesis in SZ. Our objective was to assess the magnetic resonance imaging (MRI) scans of first-episode patients and healthy controls to evaluate the frequency of CSP. The presence and the size of CSP were visually assessed on the MRI scans of 40 first-episode SZ patients, 19 nonpsychotic child and high-risk adolescent offspring of patients with SZ or schizoaffective disorder, and 59 controls. Our analysis revealed an absence of statistically significant differences in the occurrence of CSP between SZ patients, high-risk subjects, and controls. Even when the analysis was restricted to large CSP, no differences were found. Furthermore, no association between CSP and sex or handedness was observed. The absence of CSP abnormalities in first-episode SZ subjects might indicate that SZ is not characterized by developmentally mediated alterations in CSP. Also, family history of SZ might not increase likelihood for CSP.

Neuropathic pain is responsible for a significant amount of the morbidity associated with generalized and focal peripheral neuropathies. It is a consequence of alterations in neuronal function, chemistry, and structure that occur secondary to nerve injury. These manifestations of neuronal plasticity occur in the peripheral nerve, spinal cord, and brain. A variety of agents from diverse pharmacologic classes, the so-called adjuvant analgesics, have been used to treat neuropathic pain. These include antidepressants, first- and second-generation anticonvulsants, antiarrhythmic agents, topical agents, N-methyl-D-aspartate receptor antagonists, and opioid analgesics. The use of these adjuvant analgesics, either alone or in combination, should result in the alleviation of neuropathic pain in most patients. Recent advances in the understanding of pain mechanisms at multiple central nervous system levels should pave the way toward more effective treatment modalities.

What is the effect of melatonin on jet lag syndrome? Jet lag desynchronizes the internal sleep-wakefulness cycle with the environmental light/dark cycle. Advance (but not delay) of light onset is known to abolish pineal N-acetyltransferase activity and urine excretion of 6-sulphatoxymelatonin. Measurements of pineal serotonin, the substrate of melatonin biosynthesis; N-acetylserotonin (NAS), the immediate melatonin precursor; and melatonin (high-performance liquid chromatography-fluorimetric method) in the animal (rat) model of jet lag revealed that prolonged delay of darkphase onset disrupted the rhytms in comparable ways as the advance of light-phase onset. Advance of dark phase onset resulted in less severe disturbances of rhythms as compared with the advance of light phase onset. Melatonin, but not NAS, injections at the beginning of a new dark period accelerated recovery of NAS and melatonin, but not serotonin, rhythms. Spontaneously hypertensive rats were more sensitive to advance of light onset and less responsive to melatonin injections than normotensive rats. NAS and methylene blue, an inhibitor of monoamine oxidase A, attenuated light-induced disruption of NAS but not melatonin rhythms. We draw the following conclusions from our data: the beginning of the dark period may be preferable to the beginning of light period as the arrival time on eastward flights; the efficacy of melatonin in alleviating jet lag may be enchanced by administering it before, during and after rapid transition through time zones; and hypertension may exaggerate jet lag syndrome.

Community studies indicate that 19% of men and 31% of women will develop some type of anxiety disorder during their lifetime. The impact of gender is profound in that it increases the likelihood of developing an anxiety disorder by 85% in women compared to men. Sex difference in prevalence rates are apparent as early as age 6, when girls are twice as likely as boys to have an anxiety disorder. In the National Comorbidity Survey, the prevalence rates for panic disorder in women and men were 5% and 2%, respectively. Agoraphobia, which often coexists with panic disorder, has a lifetime prevalence rate of 7% in women and 3.5% in men. Prevalence of trauma is increased in young women as well, and is experienced earlier in life; 62% of sexual assaults are inflicted on females ≤18 years of age, and 29% occur in children < 11 years of age. Comorbidity of anxiety in women complicates other medical conditions as well. For example, panic disorder is highly comorbid with CHD, which remains the leading cause of death in women in developed countries. Fluctuations in reproductive hormone levels during the female life cycle is thought to be responsible for modulating anxiety. This is often implicated in the later age of onset, the more sudden and acute symptom emergence, and the more episodic course of OCD in women, and in the high prevalence (47.4%) of PMDD. Pregnancy appears to be a protective period for some anxiety disorders, including panic, while for others, such as OCD, it may be associated with onset. Hormonal changes during pregnancy, such as increased prolactin, oxytocin, and cortisol, may contribute to the suppression of stress response that occurs during this period. Despite a large and growing body of literature on anxiety disorders in general, the available data relating to women and girls falls short of informing aspects of diagnosis, treatment, and prevention that may entail sex differences. Additional work is required to understand the biological and psychosocial causes of these differences.

The deinstitutionalization of individuals with serious mental illness was driven by 4 factors: public revelations regarding the state of public mental hospitals, the introduction of antipsychotic medications, the introduction of federal programs to fund patients who had been discharged, and civil libertarian lawyers. The result is approximately 3.2 million individuals with untreated serious mental illness living in the community. Beginning in the 1970s in the United States, there began to be reported increasing incidents of violent behavior, including homicides, committed by these untreated individuals. Such incidents became more numerous in the 1980s and 1990s, and have further increased since the turn of the century. Existing studies suggest that individuals with untreated severe mental illness are responsible for at least 10% of all homicides and approximately half of all mass killings. Studies have also shown that when these individuals are treated, the incidence of violent behavior decreases significantly. Examples of treatment mechanisms that have proven effective include assisted outpatient treatment (AOT), conditional release, and mental health courts.

Cognitive impairment is considered a central feature of schizophrenia. Many aspects of cognition are impaired in schizophrenia. Careful evaluation of the relationship between cognitive impairment and the other symptoms of schizophrenia has revealed several important findings. In this article, we discuss these findings, the effects of typical neuroleptic therapy on cognitive impairment, and important issues to address in cognitive enhancement studies in schizophrenia.

Depression in children and adolescents is relatively common and associated with significant morbidity and mortality—thus, it is strongly deserving of treatment. To date, there have been a number of randomized, controlled trials of both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression in youths. Surprisingly, the available data do not demonstrate TCA superiority over placebo for this disorder in this age group. There is, however, evidence of SSRI superiority to placebo, and longer-term treatment with SSRIs may help prevent recurrence. There is almost no data on other pharmacologic approaches. Effective use of the efficacious treatments also depends on effective case-finding and providing treatment, which families and youths will take in adequate quantity and duration. The right approaches to these aspects of effective treatment are greatly understudied.

Until relatively recently the three-dimensional nature of drug molecules has been largely neglected, with approximately 25% of marketed drugs being mixtures of agents rather than single chemical entities. These mixtures are not combinations of drugs but mixtures of stereoisomers, generally racemates of synthetic chiral drugs. The individual enantiomers present in such mixtures frequently differ in both their pharmacodynamic and pharmacokinetic profiles as a result of stereochemical discrimination on interaction with chiral biological macromolecules (enzymes and receptors). The use of such mixtures may present problems if their adverse effects are associated with the less active stereoisomer or do not show stereoselectivity. In addition, interactions between enantiomers may occur such that the observed activity of the racemate is not simply the product of the effects of the individual enantiomers. Since the mid-1980s there has been an ongoing “racemate-versus-enantiomer” debate with the potential advantages of single-isomer products, including improved selectivity of action and potential increase in therapeutic index, being highlighted. As a result, regulatory authorities have issued guidelines for dealing with chiral molecules, and the number of single enantiomer agents presented for evaluation has increased. Racemic mixtures may still be developed but require justification such that the risk-benefit ratio may be assessed. In addition to new chemical entities, a number of “old” mixtures are being re-examined as potential single-isomer products, the chiral switches, with the potential for an improved therapeutic profile and possibly new indications. However, for the majority of agents currently marketed as mixtures, relatively little is known concerning the pharmacological or toxicological properties of the individual enantiomers.

A range of studies have contributed to understanding the psychobiology of emotional regulation. Functional imaging studies have demonstrated that cortico-limbic circuitry plays an important role in mediating processes such as reappraisal and suppression. Dorsolateral prefrontal cortex may be important in conscious reframing, while ventromedial prefrontal cortex and orbitofrontal cortex may be particularly important in emotion evaluation. Gene variants and early environments impact underlying emotional regulation and its neurobiology. It may be hypothesized that during interventions such as psychotherapy there are improvements in emotional regulation, together with the normalization of related psycho-biological mechanisms.

Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.

In major depression, remission rate in response to monoaminergic antidepressant is around 50%. The lack of strong synergies between classical antidepressants and psychotherapy may be due to the molecular effects of classical antidepressants. They modulate synapses but they do not substantially influence synaptogenesis. They also increase brain-derived neurotrophic factor (BDNF). However, for activity-dependent plasticity, BDNF release has to work in concert with activation of synaptogenesis. There has been considerable excitement about ketamine’s antidepressant effect. Ketamine leads to fast changes in synaptic function and plasticity that go well beyond effects of classical antidepressants. As a result, ketamine may turn out to have the capacity to considerably enhance the effects of psychotherapy. Such enhancing effects may become an important clinical indication for ketamine since its purely pharmacological effect is transient. This editorial outlines some mechanistic hypotheses, how Behavioral Activation, Trauma-Focused Psychotherapies and Humanistic Psychotherapy may specifically prolong ketamine’s antidepressant effects.

One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.