The cause of the early death of Wolfgang Amadeus Mozart (1756–1791) at the age of 35 has been the source of much discussion in the medical community. Investigators attributed to Mozart nearly 150 different medical diagnoses. However, the neurosurgical aspect of the early death of Mozart has yet to be well-analyzed, and this subject was investigated herein. The key words “Mozart” and “Mozart’s death” were searched in PubMed as well as the libraries of universities. The main source was the archive and website of Internationale Stiftung MOZARTEUM/Salzburg (www.mozarteum.at) and the cranium stored in the Internationale Stiftung Mozarteum in Salzburg/Austria. The linear fracture of the cranium is important, since it shows the neurosurgical aspect of the early death of Mozart. Mozart’s disease was most likely a neurotraumatologic one. His fracture likely occurred several months before his death, as evidenced by signs of healing. Intense headaches and declining musical performance in his last year may have been influenced by intracranial hemorrhage induced by the linear fracture. His final disease therefore may have been chronic postconcussion syndrome depending on chronic calcified epidural hematoma.

Pharmacotherapy of multiple sclerosis (MS) is evolving rapidly. Despite impressive gains over the past 2 decades in the approval of multiple drugs for MS, lack of recruitment of minorities with MS in phase 3 clinical studies is a persistent concern and skews efficacy and disability data.

Obsessive–compulsive disorder (OCD) is a chronic and disabling mental disorder characterized by the presence of obsessions and/or compulsions that cause major distress and impair important areas of functioning. About 9 out of 10 patients with OCD have comorbid psychiatric diagnoses. A high proportion of clinically diagnosed OCD patients fulfill diagnostic criteria of a schizophrenia spectrum disorder, to the point that significant evidence in the literature supports the existence and the clinical relevance of a schizo-obsessive spectrum of disorders, including schizotypal personality disorder (SPD) with OCD (schizotypal OCD). In this paper, we provide a brief but comprehensive analysis of the literature on the clinical coexistence between OCD and SPD. The clinical validity of the so-called schizotypal OCD is analyzed through a comprehensive investigation of the relationship between SPD features and obsessive–compulsive phenomena in clinical OCD samples. This review describes the potential connections between OCD and SPD on the epidemiological, sociodemographic, psychopathological, and clinical levels. SPD is commonly observed in OCD patients: about 10% of OCD patients have a full categorical diagnosis of SPD. Early clinical identification of SPD features—and, more generally, of psychotic features and personality disorders—in OCD patients is strongly recommended. In fact, a proper and early diagnosis with early treatment may have benefits for prognosis. However, although schizotypal OCD seems to have clinical and predictive validity, further neurobiological and genetic studies on etiological specificity are warranted.

Social anxiety disorder (SAD) is a common, chronic psychiatric disorder characterized by a persistent fear of social or performance situations in which embarrassment can occur. This disorder typically appears during the mid-adolescent years and is unremitting throughout life if not properly treated. SAD presents as two subtypes: the more common and debilitating generalized form, and the nongeneralized form, which consists predominantly of performance anxiety. The majority of patients with SAD have comorbid mental disorders, including mood, anxiety, and substance abuse. No single development theory has been proposed to account for the origins of SAD, although current understanding of the etiology of SAD posits an interaction between psychological and biological factors. Risk factors include environmental and parenting influences and dysfunctional cognitive and conditioning events in early childhood. The neurobiology of SAD appears to involve neurochemical dysfunction, as evidenced by studies of neuroreceptor imaging, neuroendocrine function, and profiles of response to specific medications. Clinical trials have demonstrated that benzodiazepines and antidepressants are effective in the treatment of SAD. The selective serotonin reuptake inhibitors are emerging as the first-line treatment for SAD, based on their proven safety, tolerability, and efficacy. Goals for ongoing future research include development of approaches to achieve remission, to convert nonresponders and partial responders to full responders, and to prevent relapse and maintain long-term efficacy.

This monograph explores the epidemiology, clinical presentation, and differential diagnosis of SAD, with a focus on neural circuitry of social relationships and neurochemical dysfunction. The prevalence, rates of recognition and treatment, patterns of comorbidity, quality-of-life issues, and natural history of SAD are discussed as well as pharmacologic and psychosocial treatment strategies for SAD.

Social anxiety disorder (SAD) also know as social phobia is increasingly recognized as a highly prevalent and disabling psychiatric disorder. SAD patients demonstrate cognitive-affective distortions in relation to social situations and abnormal activation patterns in limbic structures during functional imaging. Behavioral inhibition is an endophenotype that may be useful in understanding vulnerability to SAD, and that has specific imaging and genetic correlates. From an evolutionary perspective, it has been speculated that SAD represents a false appeasement alarm. It is notable that SAD responds to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors, but not to most tricyclic antidepressants; this finding is consistent with the importance of serotonin and dopamine in mediating this disorder.

While an episode of depression can first present in late life, it is more likely to be a recurrence of a disorder that began earlier in life or a continuation of a chronic form of depression. Depression in the elderly often occurs in the context of ongoing medical conditions. The treatment for these medical conditions may pose problems in treatment of depression due to increased likelihood of drug interactions. This article discusses pharmacotherapeutic and psychotherapeutic approaches to the treatment of depression in the elderly population.

The author presents two cases of nonparaphilic sexual addiction (NPSA) with comorbid depression and other psychiatric disorders in which symptoms were relieved during treatment with selective serotonin reuptake inhibitors. NPSA is defined and comorbid disorders, the neurotransmitter hypothesis of sexual function, treatment considerations, and evidence for an obsessive-compulsive disorder vs mood/affect dysregulation disorder etiology for these sexual symptoms are discussed.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was undertaken to provide a valid assessment of the differences between conventional and atypical antipsychotics and among the atypicals themselves in patients with schizophrenia. The CATIE investigators reported that while none of the study medications were ideal, olanzapine was the most effective in terms of treatment discontinuation, and there were no significant differences in effectiveness between the conventional antipsychotic perphenazine and the atypicals quetiapine, risperidone, and ziprasidone. Each drug differed slightly in rates of side effects, with more patients discontinuing perphenazine due to extrapyramidal side effects and more patients discontinuing olanzapine due to weight gain and metabolic effects. In order for data from phase 1 of the CATIE study to be interpreted within the appropriate context, physicians must understand how aspects of study design and statistical methods affect interpretation, and how this trial weighs against other data in the literature. This article enumerates the factors that complicate our understanding of the CATIE results and compares these findings with those from previously published meta-analyses. It is clear that therapeutic and side effects of antipsychotics vary from person to person. The goal of schizophrenia management is to maintain pharmacotherapeutic efficacy and tolerability over the long-term in order to maximize treatment adherence and benefits. What should emerge from CATIE is a renewed commitment to tailor schizophrenia treatment to the individual patient for long-term management.

Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

Antidepressants that primarily target the reuptake of monoamines have been highly successful treatments. However, therapies with these drugs still have several drawbacks, namely severe side effects, delays in the onset of action, and a significant percentage of non-responders. Recently, non-peptidic antagonists of the neurokinin 1 receptor, or substance P antagonists, have emerged as a novel class of drugs with antidepressant efficacy that is comparable to current drugs, but a potentially reduced side effect profile. This review summarizes the pre-clinical evidence derived from pharmacological and transgenic animal studies that suggests an important role for the substance P/neurokinin 1 system in anxiety and depression. Also, potential mechanisms by which substance P antagonists may produce their therapeutic effects are discussed.

Depression is a common, recurring illness that continues to be underdiagnosed and undertreated in both psychiatric and primary care settings. It is increasingly being recognized that painful physical symptoms, which commonly exist comorbid with depressive disorders, play a role in complicating diagnosis of depression. Patients tend to discuss physical pain with primary care physicians and emotional pain with psychiatrists, often oblivious to the fact that both may be aspects of one disorder. Those who present with somatic complaints are three times less likely to be accurately diagnosed than patients with psychosocial complaints. However, thorough evaluation of mood and anxiety disorders in primary care is sparse due to the limited time primary care physicians can spend with each patient. Better recognition and treatment of both physical and emotional symptoms associated with mood disorders may increase a patient's chance of achieving remission, which is the optimum therapeutic goal.

Abnormalities of serotonin and noradrenaline are strongly associated with depression and are thought to play a role in pain perception. Brain-derived neurotrophic factor, which is increased with antidepressant treatment, appears to influence regulation of mood and perception of pain. Clinical evidence indicates that dual-acting agents may have an advantage in modulating pain over those agents that increase either serotonin or noradrenaline alone. The novel dual-acting agents, such as venlafaxine and duloxetine, are better tolerated than tricyclic antidepressants and monoamine oxidase inhibitors. These agents have demonstrated efficacy in depression and in diabetic neuropathic pain independently. Therefore, unless otherwise stated, all inferences to studies of pain in this monograph refer to neuropathic pain in nondepressed patients.

Initial investigations of the possible interaction between schizophrenia and the immune system began in the early 1900s and have proceeded in a rather halting fashion because of the methodological challenges faced by investigators. However, a confluence of recent data suggests that activation of the inflammatory response system, the cellular immune system, and the humoral immune system may be present in some patients with schizophrenia. Some of the most compelling data support the hypothesis that minor levels of immune activation may be associated with acute psychotic exacerbations. However, a second body of evidence suggests that some individuals with schizophrenia may have chronic, evolving autoimmune processes. This article is an overview of the history, rationale, and some of the recent findings on the interaction between schizophrenia and the immune system.

Combination treatments, especially combinations of antipsychotics, are used frequently for schizophrenia, despite a paucity of evidence regarding their safety and efficacy. Because the literature basis is weak and expert recommendations are largely lacking, providers should be vigilant in documenting improved outcomes for patients thought to benefit from combination treatments. Target symptoms that have been studied include psychosis, cognitive deficits, and negative symptoms. The strongest evidence is for augmentation of clozapine with another antipsychotic or with electroconvulsive therapy for persistent positive symptoms. Combination treatments for cognitive deficits and negative symptoms are being actively investigated, but current evidence is insufficient to recommend available agents for these components of schizophrenia. It is important that appropriate monotherapies be given adequate trials before resorting to combination therapies.

What role do medications play in the overall treatment of autistic spectrum disorders? In this review, the decision-making process involving identifying symptoms, initiating a pharmacological intervention, and monitoring that process is discussed. A review of the literature with an emphasis on controlled trials in autistic spectrum disorders is also undertaken.

A major challenge in the treatment of major depressive episodes associated with bipolar disorder is differentiating this illness from major depressive episodes associated with major depressive disorder. Mistaking the former for the latter will lead to incorrect treatment and poor outcomes. None of the classic antidepressants, serotonin specific reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors have ever received regulatory approval as monotherapies for the treatment of bipolar depression. At present, there are only 3 approved medication treatments for bipolar depression: olanzapine/fluoxetine combination, quetiapine (immediate or extended release), and lurasidone (monotherapy or adjunctive to lithium or valproate). All 3 have similar efficacy profiles, but they differ in terms of tolerability. Number needed to treat (NNT) and number needed to harm (NNH) can be used to quantify these similarities and differences. The NNTs for response and remission for each of these interventions vs placebo range from 4 to 7, and 5 to 7, respectively, with overlap in terms of their 95% confidence intervals. NNH values less than 10 (vs placebo) were observed for the spontaneously reported adverse events of weight gain and diarrhea for olanzapine/fluoxetine combination (7 and 9, respectively) and somnolence and dry mouth for quetiapine (3 and 4, respectively). There were no NNH values less than 10 (vs placebo) observed with lurasidone treatment. NNH values vs placebo for weight gain of at least 7% from baseline were 6, 16, 58, and 36, for olanzapine/fluoxetine combination, quetiapine, lurasidone monotherapy, and lurasidone combined with lithium or valproate, respectively. Individualizing treatment decisions will require consideration of the different potential adverse events that are more likely to occur with each medication. The metric of the likelihood to be helped or harmed (LHH) is the ratio of NNH to NNT and can illustrate the tradeoffs inherent in selecting medications. A more favorable LHH was noted for treatment with lurasidone. However, OFC and quetiapine monotherapy may still have utility in high urgency situations, particularly in persons who have demonstrated good outcomes with these interventions in the past, and where a pressing clinical need for efficacy mitigates their potential tolerability shortcomings. In terms of maintenance therapy, adjunctive quetiapine is the only agent where the NNT vs lithium or valproate alone is less than 10 for both the prevention of mania and the prevention of depression.

It is challenging to treat symptoms of autism spectrum disorder (ASD), comorbid psychiatric disorders and ASD-associated symptoms. Some of the commonly used medications to treat these can, and frequently do have serious adverse side effects. Therefore, it is important to identify medications that are effective and with fewer side effects and negative outcomes. In this review, we looked at current evidence available for using the serotonin and norepinephrine reuptake inhibitors (SNRIs) class of medications in treating some of these often difficult to treat symptoms and behaviors. An extensive literature search was conducted using EBSCO.host. Our search algorithm identified 130 articles, 6 of which were deemed to meet criteria for the purpose of this review. Each of these six articles was independently reviewed and critically appraised. As a prototype of the SNRIs family, venlafaxine was found to be a useful adjuvant in children and adults with ASD for the treatment of self-injurious behaviors, aggression, and ADHD symptoms when used in doses lower than its antidepressant dosage. However, duloxetine was not found to show any added benefit in treatment of any of the comorbid symptoms and behaviors in ASD when compared to other antidepressants. On the other hand, milnacipran was reported to produce improvements in impulsivity, hyperactivity symptoms, and social functioning through reduction of inattention of ADHD when comorbid with ASD. Overall, SNRIs were shown variable effectiveness in treatment of these comorbid symptoms and behaviors in ASD.