This review addresses the methodologic issues relevant to the study of comorbidity and provides a broad overview of the medical and psychiatric conditions associated with migraine. Since the body of literature examining the comorbidity of migraine is enormous, the scope of this review will largely focus on community and case-control studies. Among the selected comorbid medical conditions, including disorders of the cardiovascular, respiratory, neurologic, gastrointestinal and immunologic systems, stroke, asthma, and allergies appear to be most strongly associated with migraine. Among the psychiatric illnesses, mood and anxiety disorders have been shown to be most strongly associated with migraine in the general population. Further research is indicated and necessary to elucidate the precise mechanism of migraine comorbidity.

The clinical use of mood stabilizers and antipsychotics in children and adolescents with bipolar disorders has increased significantly over the past few years. These agents have multiple effects and interactions. This articles reviews the studies that support the use of mood stabilizers and atypical antipsychotics in children and adolescents with bipolar disorders and presents information on these agent's pharmacokinetics, dosing, and drug interactions.

Vagus nerve stimulation (VNS) in humans generally refers to stimulation of the left vagus nerve at the cervical level. VNS is an established treatment largely devoid of severe side effects for medically refractory partial-onset seizures and has been used in more than 16,000 patients. Over the past 5 years, applications in other neuropsychiatric disorders have been investigated, with a special emphasis on depression. Recent data from an open-label, multi-center pilot study involving 60 patients suggest a potential clinical usefulness in the acute and maintenance treatment of drug-resistant depressive disorder. The perspective of VNS as a long-term treatment with the advantage of assured compliance makes it an interesting technique to potentially treat drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large placebo-controlled trials. Results of clinical pilot studies involving patients suffering from obesity and Alzheimer's disease indicate that VNS might induce weight loss and improve cognition. Besides its clinical usefulness, VNS can be used as a research tool, allowing neuro-physiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.

Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect γ-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

Are symptoms of daytime sleepiness relevant among patients with insomnia? Patients with insomnia frequently report daytime consequences secondary to their difficulty initiating and maintaining sleep. The purpose of this study was to determine the frequency of daytime sleepiness as defined by a self-reported measure of daytime sleepiness (the Epworth Sleepiness Scale). In addition, the study characterized the patients' psychological status using the Symptom Checklist-90-Revised. The study corroborated a relatively high frequency of excessive daytime sleepiness and psychiatric conditions among patients with insomnia. Furthermore, the results of the study suggest variation in psychological distress levels, according to the different levels of sleepiness/alertness.

The distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.

Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the adult brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy to ablate specific components of the 5-HT system in order to understand the role of different serotonergic in development of brain systems relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.

Does stress management affect psychological and immune functioning in persons with human immunodeficiency virus infections? Stress-management techniques, such as relaxation training and imagery, cognitive restructuring, coping-skills training, and interpersonal-skills training, may reduce anxiety, depression, and social isolation in HIV-infected persons by lowering physical tension and increasing a sense of control and self-efficacy. A psychoneuroimmunologic model is proposed wherein these psychological changes are hypothesized to be accompanied by an improved ability to regulate neuroendocrine functioning, which in turn may be associated with a partial normalization of immune system functions such as lymphocyte proliferation and cytotoxicity, providing more efficient surveillance of latent viruses that may contribute directly to increased HIV replication and generate opportunistic infections or cancer if left unchecked. Such a normalization of stress-associated immune system decrements are hypothesized to forestall or minimize increases in viral load and expression of clinical symptoms. This model is useful for testing the factors contributing to the health effects of stress-management interventions in HIV-infected persons. In this context, one general research strategy for testing the effects of stress-management interventions is to target them toward the more prevalent psychosocial challenges that HIV-infected people face at various points in the disease process; enroll an HIV-infected population (eg, HIV-positive homosexual and bisexual men) into a randomized trial; and monitor changes in cognitive, affective, behavioral, and social factors in parallel with hormonal, immunologic, viral, and clinical changes over the course of time. This article will review the major psychoneuroimmunologic findings that have emerged using this paradigm and suggest future research directions and clinical applications.

What biological responses characterize those acute trauma reactions that develop into chronic psychiatric disorder? The need to understand the genesis of posttraumatic psychological disorders has resulted in much attention on biological reactions in the initial aftermath of trauma exposure. This review outlines the prevailing biological models of acute stress reaction and critiques the available evidence concerning biological responses to trauma that are associated with subsequent psychological disorder. The roles of peritraumatic dissociation and vulnerability factors for acute stress reaction are also reviewed. The major challenges for research on psychobiological responses to trauma are highlighted.

What is the long-term outcome of patients with obsessive-compulsive disorder (OCD) who are treatred with exposure and response (ritual) prevention (EX/RP) alone, serotonergic medications alone, or their combination? How is the long-term outcome of these patients affected by the discontinuation? Follow-up assessments were conducted with 62 patients treated for OCD an average of 17 months posttreatment (range: 6–43 months). Patients received one of three treatments: serotonergic medications (fluvoxamine or clomipramine), intensive behavior therapy involving EX/RP, or intensive EX/RP with concurrent antidepressant medication. At follow-up, no differences in OCD symptom severity were found among the three treatment groups. However, when current medication use was taken into consideration, differences among the three treatment groups emerged. Among patients who were medication-free at the time of follow-up assessment (n=37), those in the EX/RP-alone and EX/RP-with-medication groups had lower symptom severity ratings than those in the medication-only group on 4 out of 6 measures. There were no differences in OCD severity ratings among patients taking medications at follow-up (n=25). Although these findings are interpreted with caution due to the uncontrolled nature of the study, results suggested that long-term outcome may be superior following EX/RP than following serotonergic medications, after discontinuation. For patients who remain on medications, the treatment produced benefits equivalent to EX/RP.

Can psychological factors, such as depression, affect human immunodeficiency virus progession? HIV infection is viewed as a chronic illness in which those infected often confront a number of emotional challenges and physical health and disease-related issues. Over the past 20 years, there has been increasing evidence that depression and other mood-related disturbances are commonly observed among HIV-positive individuals. There is also mounting data showing that depressive symptoms might further impact upon specific elements of immune system functioning and influence quality of life and health status. This paper will highlight studies examining the prevalence of depression during HIV infection and review some of the evidence examining the impact of depressive symptoms on immune function and HIV disease progression.

Migraine pain-relay centers, including the trigeminal ganglion, trigeminal nucleus caudalis, and thalamus, contain glutamate-positive neurons, and glutamate activates the trigeminal nucleus caudalis. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization. Glutamate receptor-subtype antagonists are effective in preclinical models of migraine, and in the clinic. These preclinical and clinical observations argue for a strong link between migraine and the glutamatergic system, a link that is important to further characterize in an effort to better understand migraine mechanisms and deliver effective therapies.

Background: We investigated clinical factors to determine their relationship to treatment resistance among bipolar patients who had a consultation at a tertiary care facility.

Methods: Patients were separated into two categories: rapid-cycling disorders and nonrapid-cycling disorders. We hypothesized that there would be less usage of lithium carbonate among nonrapid-cycling treatment-resistant patients than among rapid cyclers and also that there would be higher rates of comorbidity seen among nonrapid-cycling than rapid-cycling patients in order to account for these particular patients being treatment resistant.

Findings: Continued recyling and persistent depression characterized rapid cyclers, whereas persistent depression characterized nonrapid cyclers. Less than 30% of patients had adequate lithium treatment and there was no significant difference comparing rapid cyclers with non-rapid cyclers. Rates of comorbidity were also not significantly different between these groups. We also assessed a number of other factors.

Conclusion: Some of these factors were significant, but when a Bonferonni correction was applied, these significant differences were not maintained. The study of treatment resistance among nonrapid-cycling bipolar patients merits further research.

Does narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical “tetrad”—cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB10602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a “chronic psychotic,” while in fact they can now be properly diagnosed and treated.

Deep brain stimulation (DBS) is established as a therapy for movement disorders, and it is an investigational treatment in other neurologic conditions. DBS precisely targets neuroanatomical targets deep within the brain that are proposed to be centrally involved in the pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering the advantages of reversibility and adjustability. This might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Preclinical and clinical studies have shown effects of DBS locally, at the stimulation target, and at a distance, via actions on fibers of passage or across synapses. Although its mechanisms of action are not fully elucidated, several effects have been proposed to underlie the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. The mechanisms of action of DBS are the focus of active investigation in a number of clinical and preclinical laboratories. As in severe movement disorders, DBS may offer a degree of hope for patients with intractable neuropsychiatric illness. It is already clear that research intended to realize this potential will require a very considerable commitment of resources, energy, and time across disciplines including psychiatry, neurosurgery, neurology, neuropsychology, bioengineering, and bioethics. These investigations should proceed cautiously.

Emerging therapies for Alzheimer's disease offer hope to patients and their caregivers. Future treatments will probably include combination approaches with agents that modify amyloid processing, deposition, and clearance. One example, the AD vaccine, reduced amyloid burden and changed behavior in animal models of AD, but the human trial was halted when several subjects developed brain inflammation. Anti-inflammatory agents have epidemiologic support, but clinical trials have been disappointing, possibly related to inadequate study with anti-inflammatory agents that modify amyloid processing. Agents that target known cardiovascular risk factors, such as hypercholesterolemia, hypertension, and insulin resistance, have epidemiologic, preclinical, and clinical evidence to warrant further investigation. Heavymetal chelators, antioxidants, neurotrophic factors, glutaminergic modulators, and agents that modify hyper-phosphorylation of Tau are other approaches in research and development.