25 Aralık 2013 Çarşamba
The Year In Medicine 2013 Medscape Psychiatry Psychiatry Practice Changers: 2013 Bret S. Stetka, MD, Christoph U. Correll, MD December 18, 2013 Editor's Note: With new approvals, advances in interventional psychiatry, and an evolving appreciation of optimal psychotropic prescribing, psychiatrists had a lot to keep up with in 2013. Based primarily on Medscape Medical News coverage and input from our expert advisors, what follows are important psychiatric advances from the past year, starting with perhaps the year's most notable happening, the release of a new DSM edition. The "Bible" Gets an Update In 2013, psychiatric diagnosis underwent a major overhaul. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders  (DSM-5) was officially released at an early-morning press conference on May 18, at the American Psychiatric Association's Annual Meeting in San Francisco, California. The effort to revamp the previous edition of the manual, the DSM-IV-TR, was based on years of planning, conducting field trials, revising, soliciting public feedback, and revising again. Fifteen diagnoses were added, 2 eliminated, 28 combined, and many others amended, resulting in a net reduction of diagnoses from 172 in DSM-IV to 157 in DSM-5. The new manual features 3 major conceptual changes: removing the multiaxial system, adding a dimensional diagnostic approach, and rearranging the chapter order and grouping of disorders. The 5-axial diagnostic system of DSM-IV was removed in favor of nonaxial documentation of diagnosis in order to avoid distinction between most psychiatric disorders on the one hand and personality disorders or "mental retardation" (now "intellectual disability") on the other. Moreover, the multiaxial system was given up in order to make room for the use of clinically useful rating scales of symptom severity and impairment (that are now included in the DSM-5), instead of using a single global assessment of functioning item. The dimensional approach to diagnosis allows clinicians to rate disorders along a continuum of severity that will largely eliminate the need for "not otherwise specified (NOS)" conditions, now termed "not elsewhere defined" (NED) conditions. The dimensional diagnostic system also better correlates with identifying treatment needs and implementing treatment. By listing disorders that are neurobiologically more closely related next to each other, the revised chapter order is intended to better reflect advances in the understanding of underlying disease vulnerabilities, as well as symptom characteristics of mental health disorders. Most of the criteria included in DSM-5 remain identical, or similar, to those in DSM-IV. However, significant updates were made, including: • The requirement of increased energy/goal-directed behavior as an A criterion in addition to either irritability or expansive mood to diagnose a manic episode; • The replacement of a mixed episode (ie, the full syndromal overlap of mania and major depressive episode) with a mixed specified (ie, admixture of at least 3 of the more specific symptoms of the opposite polarity); • Addition of the "with anxious distress" specifier that allows clinicians to highlight clinically relevant anxiety even below the level of a syndromal anxiety disorder in patients with a manic, hypomanic, or depressive episode; • Addition of disruptive mood dysregulation disorder under the depressive disorders section, a hotly debated diagnosis hoped to decrease inappropriate diagnoses of bipolar disorder in youth with chronic mood dysregulation and onset of symptoms between age 6 and 9; • Grouping of autistic disorder, Asperger disorder, and pervasive developmental disorder under 1 category -- "autism spectrum disorder" -- giving the symptom severity and functional level more weight in differentiating individual presentations; • Elimination of substance dependence and introduction of the substance-use disorder (or substance-related and addictive disorders) classification with degrees of severity that are not contingent on physical withdrawal signs and symptoms, which can occur with medications that are not abused or which can be largely absent despite of heavy marijuana use; • Addition of the hotly debated attenuated psychosis syndrome, not only under "Conditions for Further Study" but also under "Other Specified Schizophrenia Spectrum and Other Psychotic Disorder" in the regular Section II; and • Addition of binge-eating disorder and premenstrual dysphoric disorder, as well as expansion of the criteria for post-traumatic stress disorder by a fourth symptom cluster, by dividing the avoidance/numbing cluster into 2 distinct clusters, such as avoidance and persistent negative alterations in cognitions and mood. For more on the new manual, have a look at Medscape's guide to DSM-5. DSM-5: The Controversy The DSM update was not without controversy -- a lot, in fact. Some originally proposed criteria drew so much public and professional criticism that they were ultimately withdrawn from the final draft, or included in an appendix of conditions on which more study is needed. Leading up to the manual's release, a number of leading psychiatrists -- DSM-IV Task Force chair Allen Frances, MD, in particular -- were not shy about expressing their concerns with the new manual. "My great fear is that DSM-5 will inappropriately expand the boundaries of psychiatry and increase our already existing problem of diagnostic inflation. This will result in inappropriate medication use, unnecessary stigma, and the misallocation of scarce mental health resources," said Dr. Frances in a Medscape interview. Among the most hotly debated additions to the DSM-5 were the mixed specifier to a manic or hypomanic or major depressive episode, the disruptive mood dysregulation disorder (DMDD), and the attenuated psychosis syndrome. Although an admixture of at least 3 of the more specific criteria of (hypo)mania to symptom constellations fulfilling full major depressive disorder (MDD) criteria have been predictive of conversion from MDD to bipolar disorder, there has been a concern that data are insufficient to guide clinicians regarding the best treatment strategies of such patients. In this context, it has been concerning that the reliability of the principally unchanged MDD and generalized anxiety disorder diagnoses in the American Psychiatric Association (APA) field trials landed in the lower half of the range for questionable agreement. The introduction of DMDD into the depressive disorders section of DSM-5 was also hotly debated. This decision was based on studies finding that the long-term outcome of youth with frequent, nonepisodic, irritability, anger, and temper outbursts without euthymic interepisode intervals was not bipolar disorder, but rather MDD. These data motivated the desire to reduce potentially inappropriate bipolar disorder diagnoses in children and adolescents. However, it has been pointed out that DMDD overlaps largely with oppositional defiant disorder (a condition that as per DSM-5 cannot be codiagnosed with DMDD) and that the reclassification from bipolar disorder or mood disorder not otherwise specified to DMDD may not reduce clinician's practice of treating irritability and aggression with antipsychotics (also see below). Moreover, if nonepisodic mood dysregulation is not part of bipolar disorder, it is difficult to understand why the onset of such symptoms is restricted in DSM-5 to ages 6-9, rather than extending to the entire prepubertal period or even until age 17. In the field trials, again, DMDD landed in the lower half of the range for questionable agreement. Finally, the addition of the attenuated psychosis syndrome under conditions requiring further study in Section II was welcome, as longitudinal studies collected in research centers suggested that attenuated psychotic symptoms with onset or worsening in the past 12 months predicted development of full psychosis. However, it has been bemoaned as being premature that this nonpsychotic -- and more often than not, nonspecific -- syndrome, which places maximally 1 out of 3 individuals at risk for conversion to full-blown psychosis over 3 years, was also listed as an example for "Other Specified Schizophrenia Spectrum and Other Psychotic Disorder" in Section II. The concern is that clinicians will not have the time nor expertise to use the research criteria in the same way as performed in dedicated high-risk clinics, and that patients may be overdiagnosed, stigmatized, and overtreated. APA representatives stood firm on their position that although the manual might not be perfect, until the state of research allows psychiatric diagnosis to be based on more scientific and biologically based criteria, symptom-based diagnosis remains the gold standard of science and thus justifies the revised manual. Medscape contributor (and at the time APA president-elect) Jeffrey A. Lieberman, MD, wrote in a Medscape editorial, "The fact that we have not seen sufficient progress in scientific research to enable greater change in psychiatric diagnosis is not the fault of the DSM. Psychiatrists would like nothing more than to see laboratory tests and imaging -- routine in diagnosing other diseases -- incorporated into the DSM and clinical practice." Because, overall, the DSM-5 criteria are not that different from DSM-IV criteria, most clinicians have not had a very difficult time switching to DSM-5 criteria, except for some of the more debated diagnoses described above. Antipsychotic Use Evolves Psychiatrists periodically come under fire for overprescribing antipsychotics, potent medications with potentially serious long-term side effects. However, when used properly, the agents are very effective, and in some cases lifesaving. To this end, a number of studies and reports published this year helped evolve and optimize antipsychotic prescribing and identify patient populations in whom these agents are more or less appropriate. In September, a list of 5 key antipsychotic prescribing recommendations was released by the APA to address prescribing patterns considered outside of standard practice. The report is part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely® campaign, an initiative to curb unnecessary or potentially harmful medical practices. The new recommendations are: 1. Don't prescribe antipsychotic medications to patients for any indication without appropriate initial evaluation and appropriate ongoing monitoring; 2. Don't routinely prescribe 2 or more antipsychotic medications concurrently; 3. Don't use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia; 4. Don't routinely prescribe antipsychotic medications as a first-line intervention for insomnia in adults; and 5. Don't routinely prescribe antipsychotic medications as a first-line intervention for children and adolescents for any diagnosis other than psychotic disorders. Joel Yager, MD, chair of the APA's Council on Quality Care, told Medscape Medical News, "The point isn't to say that some of this prescribing should never occur but that it shouldn't be done routinely as an initial practice when there are evidence-based alternatives that are safer and may be less costly." Antipsychotic use in elderly patients has drawn particular concern in recent years given that these agents are associated with increased risk for falls and cognitive decline. Moreover, although antipsychotics can reduce agitation and aggression, they have a black box warning for increased mortality compared with placebo, based on pooled placebo-controlled data. According to the Centers for Medicare & Medicaid Services (CMS), in 2010, over 17% of nursing home residents had daily antipsychotic doses exceeding recommended levels. In response to trends such as this, in 2012 the agency launched the National Partnership to Improve Dementia Care, with the goal of reducing antipsychotic use in nursing homes by 15% by the end of 2013. Preliminary results are encouraging. According to CMS, the national prevalence of antipsychotic use in nursing home residents fell by 9.1% in the first quarter of 2013. In related news, a literature review  published in April reported that most seniors with dementia who are taking an antipsychotic to control neuropsychiatric symptoms such as agitation, aggression, and hallucinations can be taken off these medications without relapsing. Prescribing antipsychotics to pediatric patients has also raised governmental concerns. In August, the US Department of Health and Human Services' Office of Inspector General (OIG) launched an investigation into the prescribing of atypical antipsychotics to children covered under Medicaid. Concern over antipsychotic use in children and adolescents stems from findings such as those published in the March issue of Psychiatric Services, which showed that from 1997 to 2006, use of antipsychotic medications in Medicaid-insured children from low- or very-low-income families increased 7- to 12-fold. Moreover, a study of outpatient mental health visits reported that between 1995-1998 and 2007-2010, visits with a prescription of antipsychotic medications per 100 persons increased from 0.14 to 1.73 (odds ratio, 6.35) for children and from 0.76 to 3.81 (odds ratio, 5.45) for adolescents. However, according to a study published in Pediatrics, at least in very young children (2-5 years old), the increased use of psychotropics seems to have leveled off since the mid-2000s, a time when the use of psychotropic prescription drugs to treat attention-deficit/hyperactivity disorder (ADHD), mood disorders, anxiety, and other mental health disorders had reached record highs. Nevertheless, the prescribing recommendation released by the APA as part of the Choosing Wisely campaign, calling for not routinely prescribing antipsychotic medications as a first-line intervention for children and adolescents for any diagnosis other than psychotic disorders, has also been met with criticism. Although overprescribing of antipsychotics for youth is clearly not desired in those with disruptive behavior disorders without adequate prior treatment with nonpharmacologic, psychosocial, and family interventions, the recommendations neglected US Food and Drug Administration (FDA) approval and sound efficacy and tolerability data for antipsychotics for pediatric bipolar mania and irritability in the context of autistic disorder. Moreover, although over- and misprescribing of psychotropic drugs is a possibility that needs to be identified and rectified, findings  published earlier this year in JAMA Psychiatry point to the fact that when used properly, psychotropic medications can be very effective. The study, an analysis of FDA Summary Basis of Approval (SBA) reports on more than 92,000 patients with mental illness, found that although severe psychiatric illnesses, such as schizophrenia and major depression, are associated with an increased mortality risk, psychotropic medication prescribed for these disorders appears to reduce this risk. In fact, the overall mortality was lower among patients with schizophrenia who were assigned to antipsychotics, including haloperidol second-generation antipsychotics, compared with patients with schizophrenia who were assigned to placebo. The same result was true for patients with depression and bipolar disorder who were randomly assigned to active drug vs placebo. Altogether, treatment with modern psychotropic drugs decreased mortality risk by 25% to 70%. In the context of antipsychotic prescribing for a broad range of psychiatric disorders, it is important to weigh the generally relatively small and difficult-to-predict differences in efficacy with the generally larger and more generalizable differences in adverse effects. A multiple-network meta-analysis of antipsychotics in the short-term treatment of schizophrenia contributed detailed meta-analytic calculations of antipsychotic efficacy and, especially, of key antipsychotic adverse effects to the evidence base, such that clinicians can discuss options with patients and families and make treatment decisions. New Approvals Two 2013 drug approvals expanded the antidepressant toolkit. In July, the FDA approved the serotonin-norepinephrine reuptake inhibitor (SNRI) levomilnacipran (Fetzima™) for MDD in adults, based on data from 3 pivotal, phase 3 randomized, placebo-controlled trials. The drug is the fourth SNRI to be approved in the United States. In vitro studies show levomilnacipran to be the most noradrenergically active of the SNRIs, with a 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition, and 17-27 times higher selectivity for norepinephrine reuptake inhibition compared with venlafaxine and duloxetine, respectively. The efficacy of extended-release levomilnacipran vs placebo has been established at doses of 40 mg/day, 80 mg/day, and 120 mg/day. The most common adverse effects in clinical trials included nausea (17%), constipation (9%), hyperhidrosis (9%), tachycardia (6%), erectile dysfunction (6%), tachycardia (6%), palpitations (5%), and vomiting (5%). Adverse event rates were generally consistent across doses (40-120 mg); the only dose-related adverse events were urinary hesitation and erectile dysfunction. Of note, levomilnacipran is neither a substrate for nor potent inhibitor of cytochrome P450 isoenzymes, but rather is eliminated renally. Thus, it can be used in patients with severe liver damage, but it is not recommended in patients with end-stage renal disease. Because of its selective noradrenergic potency, levomilnacipran is theoretically potentially useful for subsets of depressed patients with prominent fatigue and anergia. However, if this efficacy potential is realized, clinical practice remains to be seen. Later this year, both the FDA and the European Medicines Agency's Committee for Medicinal Products for Human Use approved vortioxetine (Brintellix™) for the treatment of major depressive episodes in adults. Vortioxetine is considered a new multimodal antidepressant. In vitro studies indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist; a 5-HT1A receptor agonist; a 5-HT1B receptor partial agonist; and an inhibitor of the 5-HT transporter. This mechanism of action leads to enhanced and brain-region-specific neurotransmission of multiple neurotransmitter systems, including serotonin, noradrenaline, dopamine, glutamate, acetylcholine, and histamine. The recommended starting dose is 10 mg orally once daily, taken at any time. The dose should then be increased to 20 mg/day, as tolerated. If higher doses are not tolerated, doses down to 5 mg can be used. Data from 6 of 8 short-term, placebo-controlled studies in the initial pivotal program, conducted internationally, demonstrated significant efficacy of vortioxetine in a dose range from 5 to 20 mg/day but most consistently at doses of 15-20 mg/day. In one of these studies, acute antidepressant efficacy was also demonstrated at 5 mg/day in an elderly population (mean age, 70.6 years).[10-13] Two low-dose studies, (2.5 mg/day and 5 mg/day of vortioxetine) did not separate the efficacy of the drug from placebo.[14,15] The most common adverse effects of vortioxetine across multiple studies were nausea (21%-32%), headache (15%-17%), diarrhea (7%-10%), and dry mouth (6%-8%), but these adverse effects were generally transient and dropout rates were low. Finally, based on the mechanism of action, vortioxetine is being studied for potentially beneficial effects on cognitive dysfunction as part of MDD, with promising initial results, such as from the recently completed FOCUS study. In this study of MDD patients, vortioxetine 10 mg and 20 mg were each significantly superior to placebo on the predefined primary composite cognitive outcome. Moreover, in path analyses, cognitive improvements appeared to be independent of the improvement in depressive symptoms and were also apparent in nonresponders and nonremitters. Psychiatry Meets Genomics A study  published in February in the Lancet reported genetic links between 5 psychiatric disorders: autism spectrum disorder, ADHD, bipolar disorder, MDD, and schizophrenia. The work was conducted by investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of mental illness to day. Results of this genome-wide association study found that single-nucleotide polymorphisms in 2 genes involved in neuronal calcium balance -- CACNA1C and CACNB2 -- are involved in these disorders. The findings suggest that targeting voltage-gated calcium-channel signaling could be a potential therapeutic avenue in psychiatric illness. Building on this research, the same group published a follow-up study in August in Nature Genetics. They compared genome-wide genotype data for thousands of people with 1 of the same 5 conditions vs data from control individuals, and calculated the extent of genetic overlap among the illnesses. As Medscape Medical News reported, researchers found that "the overlap in heritability attributable to common genetic variation is about 15% between schizophrenia and bipolar disorder, about 10% between bipolar disorder and depression, about 9% between schizophrenia and depression, and about 3% between schizophrenia and autism." Although the unraveling of the genetic code and increasingly cheap, high-throughput technology has dramatically increased the amount and granularity of genetic studies, the increase in available data has been paralleled by higher degrees of complexity. This is particularly the case in psychiatric disorders, which are polygenic and also influenced by trauma and other gene-environment interaction effects. Furthermore, the genes that have been identified seem to be coding for circuits and global processes involved in many mental operations and disorders. This lack of specificity suggests that either the combination of genetic defects and/or timing and epigenetic effects work in concert to produce certain symptoms and syndromes currently classified clinically as groups of disorders. Thus, more research is needed in order to understand the overlap and more unique genetic and functional contributions to different psychiatric disorders and, especially, the relevance of these findings for the development of therapeutic or preventive interventions. Psychedelic Therapy? Ketamine, a long established anesthetic and psychedelic street drug, which acts as a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, is increasingly being taken seriously as an antidepressant. Since 2000, a series of placebo-controlled crossover studies pointed to the rapid-onset antidepressant effect of a single dose of intravenous ketamine, starting within the first hour after the injection, peaking at 24 hours, and lasting up to 3-5 days. However, these robustly positive results have been questioned, as it is almost impossible to blind patients who receive either placebo or a subanesthetic dose of ketamine. Therefore, it was important to rule out the possibility of functional unblinding and expectation effects by using another anesthetic as a comparator. This year, researchers confirmed ketamine's efficacy in what is currently the largest study, reporting in the American Journal of Psychiatry that it improved depression in 64% of patients within 24 hours of administration, whereas the anesthetic midazolam only improved symptoms in 28% of patients. Although experts, including the study investigators, acknowledge that it is too early to recommend a major change in practice, these results are encouraging in terms of understanding the biology of depression and representing a potential therapeutic approach worth further study. In particular, future studies are needed that investigate alternative routes of administration as well as alternative agents that do not have the potentially adverse brain effects of repeated ketamine administrations. A number of other studies this year also furthered the understanding of ketamine's therapeutic potential. A study  published in the May issue of Journal of Psychopharmacology honed ketamine dosing: Serial infusions at dosages lower than are commonly used are more effective than single infusions in treating depression symptoms. Other work identified biomarkers that can potentially predict the antidepressant effects of ketamine, while a small study of 15 adults with a moderate to severe obsessive compulsive disorder (OCD) showed a 50% responder rate for OCD symptoms 7 days after receiving a single intravenous ketamine infusion; a 40% responder rate was reported 2 weeks post-treatment. The renewed interest in psychedelics as therapeutic agents doesn't stop with ketamine. Decades after Timothy Leary's somewhat infamous experiments with LSD, researchers are once again probing the potential utility of not just acid, but also psilocybin, mescaline, or peyote. A study from August published in PLoS One looked at nearly 22,000 psychedelic drug users and found no link between any of these agents and mental illness. In fact, use of the agents was associated with a lower rate of psychiatric symptoms. On the other hand, multiple studies have demonstrated that certain substances, including cannabis, amphetamines, and alcohol, can have detrimental psychiatric effects. For example, in a large, nationwide Finnish study of 18,478 patients with substance-induced psychotic disorders, the 8-year rate of conversion to schizophrenia was highest in cannabis users (46%), followed by amphetamine (30%) and alcohol (5%) users. Moreover, the risk for progression to schizophrenia was highest in the first 3 years, especially in cannabis users. Nevertheless, even within cannabis, there are ingredients that seem to have beneficial psychiatric effects. For example, cannabidiol seems to have therapeutic actions via boosting of anandamide levels, which presents another target for drug development. Thus, because substances of abuse have powerful effects on mental functioning, future research should target and dissect these effects and underlying mechanisms in order to identify viable targets for the development of therapeutic agents. A New Psychiatry Subspecialty? If this year is any indication, psychiatrists are poised to become interventionalists. Interventional psychiatry is an emerging subspecialty that uses brain stimulation techniques to alter the dysfunctional neurocircuitry underlying psychiatric diseases. Although the field of psychiatry does not yet officially recognize interventionalists or offer formal training and certification, there is increasing interest in the field, and 2013 saw a host of "stimulating" findings on various interventional approaches to mental illness. Two transcranial magnetic stimulation (TMS) devices, including one approved this past January, are now approved for the acute treatment of depressed patients who have failed to respond to at least 1 antidepressant. Findings  presented at the American Psychiatry Association's 2013 Annual Meeting found that TMS induced statistically and clinically meaningful response and remission in patients with resistant depression during the acute phase; the results were maintained at 52 weeks. A small, randomized controlled trial  of 27 adults, published in Biological Psychiatry, demonstrated TMS to be effective in improving cognitive deficits in schizophrenia Deep brain stimulation (DBS) is also being investigated for psychiatric applications, including treatment-resistant depression, OCD, and anorexia nervosa. Work  published in the Lancet in March was the first to assess DBS in anorexia. The study was small, including only 6 participants, and was intended to demonstrate the safety of DBS. Not only was the approach shown to be safe, but half of the patients showed improvement in mood and body mass index over baseline after the procedure. Finally, 2 direct nerve stimulation techniques showed promise this year. A study  of 70 patients published in Brain Stimulation suggests that vagus nerve stimulation is effective in treatment-resistant depression and may actually induce metabolic changes in the cortical regions associated with depression. Other work  presented at the APA Annual Meeting reported that trigeminal nerve stimulation may be an effective treatment option for ADHD. Following treatment, previously treatment-naive patients between 7 and 14 years old demonstrated improvements in patient-, parent-, and investigator-reported ADHD symptoms and executive function, as well as on computerized cognitive testing. Clearly, more research is needed on these techniques as well as on less invasive alternatives with similar effects.