Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan

This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed.     

Effects of different antidepressant treatments on the core of depression

Core symptoms of depression are a combination of psychological and somatic symptoms, often combined with psychomotor and cognitive disturbances. Diagnostic classification of depression including the concepts of melancholic, endogenous, or severe depression describe severely depressed patients suffering from most of the core symptoms, together with clinical characteristics of a cyclic unipolar or bipolar course, lower placebo response rates, higher response rates to electroconvulsive therapy, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of hypothalamic-pituitary-adrenal axis hyperactivity and specific electroencephalographic patterns have also been shown in this patient group. Summarizing the symptomatology of depression in these patients, a broad overlap between the abovementioned subgroups can be suggested. Because the positive diagnosis of those core symptoms of depression may include clinical consequences, it would be of use to integrate all the mentioned concepts in the upcoming new versions of the diagnostic systems DSM-V and ICD-11.     

Medication dependence and anxiety

Anxiety disorders are common and costly psychiatric illnesses. Pharmacological treatment was enhanced with the introduction of benzodiazepines, which proved safer and more effective than older drugs. The risk of dependence, however, has made clinicians reluctant to use these medications. In fact, few patients appear to develop significant difficulties with these drugs, given how widely they are used. Careful planning for discontinuation of therapy is important. In addition, for some individuals, there appears to be a complex and as yet unelucidaied relationship between dependence on drugs or alcohol and anxiety. The newer antidepressants offer efficacy without abuse or dependence liability, but are expensive and have side effects that are intolerable for some patients. Pharmacological therapy for anxiety should be prescribed and managed so as to minimize any existing risk, while aiming to restore the patient to wellness in terms of symptoms and function.     

Genetics of drug dependence

Drug-dependence disorders (we focus here on cocaine, opioid, and nicotine dependence) are genetically influenced. Risk genes have been located based primarily on genetic linkage studies, and identified primarily based on genetic association studies. In this article we review salient results from linkage, association, and genome-wide association study methodologies, and discuss future prospects for risk allele identification based on these, and on newer, methodologies. Although considerable progress has been made, it is likely that the application of more extensive sequencing than has previously been practical will be required to identify a fuller range of risk variants.     

SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence

Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. Our objective was to measure caffeine effects on cerebral perfusion in humans using single photon emission computed tomography, with a specific focus on areas of reinforcement and reward. Two groups of nonsmoking subjects were studied, one with a low (8 subjects) and one with a high (6 subjects) daily coffee consumption. The subjects ingested 3 mg/kg caffeine or placebo in a raspberry-tasting drink, and scans were performed 45 min after ingestion. A control group of 12 healthy volunteers receiving no drink was also studied. Caffeine consumption led to a generalized, statistically nonsignificant perfusion decrease of 6% to 8%, comparable in low and high consumers. Compared with controls, low consumers displayed neuronal activation bilaterally in inferior frontal gyrusanterior insular cortex and uncus, left internal parietal cortex, right lingual gyrus, and cerebellum. In high consumers, brain activation occurred bilaterally only in hypothalamus. Thus, on a background of widespread low-amplitude perfusion decrease, caffeine activates a few regions mainly involved in the control of vigilance, anxiety, and cardiovascular regulation, but does not affect areas involved in reinforcing and reward.     

Pharmacologic treatment of schizophrenia

Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.     

Psychosis in children: diagnosis and treatment

The diagnosis of childhood psychosis raises a host of unresolved problems, despite the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) giving identical symptoms and definitions for children, adolescents, and adults. The fantasy lives of children, and issues of developing language and cognition (including retardation), all impair diagnostic accuracy, particularly when differentiating between childhood-onset schizophrenia (COS) (≤12 years), bipolar affective disorder, major depressive disorder, and even obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: the catch-all classification, psychosis not otherwise specified (PNOS), is always available for conundra that prove unsolvable. Typical if nonpathognomonic features include neurocognitive difficulties. Multiple screening instruments and specialized versions of semistructured diagnostic interviews are available. Although smooth-pursuit eye-tracking movements may prove a genetic marker for COS, etiologies are likely to be oligogenetic rather than related to a single gene. No specific biological markers or neuroimages have been identified. As such, psychoses may be indicative of a more general pattern of brain dysfunction. Drug treatments are largely based on the adult literature because of a dearth of controlled data below age 18. There are still no rigorous studies of psychosocial treatments and psychotherapy specific to childhood psychosis.     

Alcoholism: the dissection for endophenotypes

Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.     

Nonpharmacological treatments for anxiety disorders

An evidence-based review of nonpharmacological treatments for anxiety disorders is presented. The vast majority of the controlled research is devoted to cognitive behavior therapy (CBT) and shows its efficiency and effectiveness in all the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) anxiety disorders in meta-analyses. Relaxation, psychoanalytic therapies, Rogerian nondirective therapy, hypnotherapy and supportive therapy were examined in a few controlled studies, which preclude any definite conclusion about their effectiveness in specific phobias, agoraphobia, panic disorder, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD), CBT was clearly better than psychoanalytic therapy in generalized anxiety disorder (GAD) and performance anxiety Psychological debriefing for PTSD appeared detrimental to the patients in one high-quality meta-analysis. Uncontrolled studies of psychosurgery techniques for intractable OCD demonstrated a limited success and detrimental side effects. The same was true for sympathectomy in ereutophobia. Transcranial neurostimulation for OCD is under preliminary study. The theoretical and practical problems of CBT dissemination are discussed.     

Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.     

Mechanism-based treatments for Alzheimer's disease

Treatment for Alzheimer''s disease is entering a new and exciting phase, with several new drugs beginning clinical trials. Many of these new therapies are based on our best current understanding of the pathogenesis of Alzheimer''s disease, and are designed to try to either slow or halt the progression of the disease. There are several different theories underlying the current efforts, and these are briefly reviewed. Therapies directed against some aspect of β-amyloid formation, against neurofibrillary tangle formation and against the inflammatory response are all considered, as are the problems associated with each area. It is as yet unclear which, if any, of these approaches will be successful, but the high level of activity in each of these three fields provides some hope that an effective treatment for Alzheimer''s disease is on the horizon.     

Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications

The majority of individuals with depression experience sleep disturbances. Depression is also over-represented among populations with a variety of sleep disorders. Although sleep disturbances are typical features of depression, such symptoms sometimes appear prior to an episode of depression. The bidirectional associations between sleep disturbance (especially insomnia) and depression increase the difficulty of differentiating cause-and-effect relationships between them. Longitudinal studies have consistently identified insomnia as a risk factor for the development of a new-onset or recurrent depression, and this association has been identified in young, middle-aged, and older adults. Studies have also observed that the combination of insomnia and depression influences the trajectory of depression, increasing episode severity and duration as well as relapse rates. Fortunately, recent studies have demonstrated that both pharmacological and nonpharmacological interventions for insomnia may favorably reduce and possibly prevent depression. Together, these findings suggest that sleep-related symptoms that are present before, during, andlor after a depressive episode are potentially modifiable factors that may play an important role in achieving and maintaining depression remission.     

Treatment goals: response and nonresponse

Psychiatric symptomatology is often subjective, but it can be partly made more objective for the purposes of evaluation. Esquirol was the first modern psychiatrist to stress the need for a scientific approach to treatment evaluation. The kinetics of treatment is complex because different components of the clinical picture improve at a different pace. Assessment of treatment requires prior definition of end point, response, and nonresponse. Response is influenced by several factors, such as placebo effect, diagnostic category and subtypes, and patient heterogeneity. Treatment response may be predicted from clinical and biological parameters. This article lists the main causes of nonresponse, and suggests how to remedy them.     

Diagnosis and treatment of sleep disorders: a brief review for clinicians

Sleep disorders encompass a wide spectrum of diseases with significant individual health consequences and high economic costs to society. To facilitate the diagnosis and treatment of sleep disorders, this review provides a framework using the International Classification of Sleep Disorders, Primary and secondary insomnia are differentiated, and pharmacological and nonpharmacological treatments are discussed. Common circadian rhythm disorders are described in conjunction with interventions, including chronotherapy and light therapy. The diagnosis and treatment of restless legs syndrome/periodic limb movement disorder is addressed. Attention is focused on obstructive sleep apnea and upper airway resistance syndrome, and their treatment. The constellation of symptoms and findings in narcolepsy are reviewed together with diagnostic testing and therapy, Parasomnias, including sleep terrors, somnambulism, and rapid eye movement (REM) behavior sleep disorders are described, together with associated laboratory testing results and treatment.     

Behavioral and psychological signs and symptoms of dementia: a practicing psychiatrist's viewpoint

Alzheimer's disease typically presents with two often overlapping syndromes, one cognitive, the other behavioral. The behavioral syndrome is characterized by psychosis, aggression, depression, anxiety, agitation, and other common if less well-defined symptoms subsumed under the umbrella entity "behavioral and psychological symptoms of dementia" (BPSD), itself divided into a number of subsyndromes: psychosis, circadian rhythm (sleepwake) disturbance, depression, anxiety, and agitation, it is BPSD with its impact on care providers that ultimately precipitates the chain of events resulting in long-term institutional care. The treatment challenge involves eliminating unmet medical needs (undiagnosed hip fracture and asymptomatic urinary tract infection or pneumonia). Pharmacologic intervention relies on risperidone and, increasingly cholinesterase inhibitors for the control of psychosis (but with response rates of only 65% at tolerable doses), olanzapine and risperidone for anxiety, and carbamazepine and valproic acid for agitation. However, evidence increasingly favors nonpharmacologic interventions, to the extent that these should now be considered as the foundation of BPSD treatment. Problem behaviors are viewed as meaningful responses to unmet needs in the therapeutic milieu. Because the progression and impact of BPSD varies between patients, interventions must be explored, designed, implemented, and assessed on an individual basis. They include: family support and education, psychotherapy reality orientation, validation therapy, reminiscence and life review, behavioral interventions, therapeutic activities and creative arts therapies, environmental considerations (including restraint-free facilities), behavioral intensive care units, and workplace design and practices that aid the ongoing management of professional caregiver stress.     

Developments in antipsychotic therapy with regard to hypotheses for schizophrenia

The typical antipsychotic drugs like chlorpromazine and haloperidol were discovered by serendipity in the 1950s. A number of so-called "me too" drugs with similar chemical structures and modes of action were marketed in the subsequent years. The first atypical antipsychotic, clozapine, was an exception because it lacked some of the pharmacological properties of the typical antipsychotics related to the extrapyrimidal motor system. This unique feature of clozapine significantly broadened understanding of the mode of action of antipsychotics, and created new hypotheses for schizophrenia. Hypothesis-orientated development of new drugs was only recently initiated. Abnormalities of the immune system in schizophrenia are being increasingly discussed: shifts in the levels of T helper cells subsets 1 and 2 (Th1 and Th2) have been observed, and studies with risperidone and the cyclooxengenase (COX2) inhibitor celecoxib as an add-on therapy have provided very promising results. The glutamate N-methyl-D-aspartate (NMDA) receptors have also been investigated in relation to neuropathological abnormalities in prefrontal areas of the brain of patients with schizophrenia. This may lead to new technologies like artificial networks related to the glutamate NMDA receptor system. New molecular biological techniques used in pharmacogenomics and proteomics offer new and exciting directions for future drug developments.     

Neurobiologically informed treatment for adults with anorexia nervosa: a novel approach to a chronic disorder

Anorexia nervosa (AN) is a severe and debilitating disorder with significant medical and psychological sequelae. To date, there are no effective treatments for adults, resulting in high rates of chronicity, morbidity, and mortality. Recent advances in brain imaging research have led to an improved understanding of etiology and specific neurobiological mechanisms underlying symptoms. Despite this, there are no treatments focused on targeting symptoms using this empirically supported mechanistic understanding of the illness. Updated treatment approaches focused on targeting neurobiological mechanisms underlying core AN symptomatology are necessary to improve treatment out-comes for this population. Neurobiologically Enhanced With Family Eating Disorder Trait Response Treatment (NEW FED TR) is a neurobiologically informed treatment targeting key temperament constructs associated with the illness through the delivery of psychoeducation and skills training to patients and nominated carers.     

Therapeutic options and challenges for substances of abuse

Addiction to substances continues to be a significant public health concern in the United States. The following review of current pharmacological treatments discusses a range of substances: nicotine, alcohol, cocaine, and opioids. The goal is to provide an overview of currently available and new pharmacological treatments for substance use disorders, while also addressing the pharmacotherapeutic challenges remaining. The significant advances in pharmacotherapy have had limited utilization, however. For example, naltrexone for alcoholism is infrequently prescribed, buprenorphine for opiates still has relatively few qualified prescribers, and stimulants have no Food and Drug Administration-approved pharmacotherapy. These pharmacotherapies are needed, with the rate of even the relatively uncommon abuse of opiates now rising sharply.     

New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum

Maternal perinatal mental health has enormous consequences for the well-being of the mother, her baby, and the family. Although it is well documented that perinatal depression is both common and morbid, with a prevalence of 10% to 15% in the general population, there remain many critically important unanswered questions about the pathogenesis of perinatal depression and most effective treatment regimens. Current lines of evidence from both human and animal models implicate hormonal dysregulation, abnormalities in hypothalamic-pituitary-adrenal axis activity, and the contributions of genetics and epigenetics as playing key roles in the development of perinatal reproductive mood disorders. Investigations into both human and animal models of perinatal depression offer much promise for the future identification of the underlying pathophysiology and subsequent early identification and/or prevention and appropriate treatment for women at risk for postpartum depression. Lastly, although it is generally accepted that pregnancy is not protective with regard to new onset or relapse of depression, the way to best treat maternal depression during pregnancy and lactation remains hotly debated. Future research in this area will more clearly elucidate the underlying pathogenesis, the potential long-term impact of perinatal depression on the developing fetus, and how best to counsel pregnant women about the risks of untreated major depressive disorder versus the risks of psychopharmacologic treatment during pregnancy and lactation.     

Role of melatonin in the induction and maintenance of sleep

Pharmacokinetic studies of melatonin in young and elderly human volunteers, and the measurement of hypnotic effects in chicks under alternate light-dark or permanent light conditions, show that melatonin is a bioprecursor of hypnotic acetyl metabolites produced by the enzymatic acetylation of both melatonin and 2-oxomelatonin under the control of serotonin N-acetyltransferases (NATs), which are present in the pineal gland. The acetyl metabolite of melatonin, which we call carbo2, is an N-acetyl-β-carboline. The electroencephalographs (EEG) architecture of the sleep produced by this compound is similar to thai of physiological sleep, and is characterized by the significant proportion of slow-wave deep sleep and rapid eye movement sleep. This is in sharp contrast to the EEG sleep architecture observed with GABAergic (GABA, γ-aminobutyric acid) compounds. Since insomnia and sleep disorders are believed to be due to a lack of NAT enzymes in the pineal gland, a new therapeutic approach of sleep disorders by administration of such hypnotic acetyl metabolites of melatonin, or synthetic analogs thereof, can be en visaged.