Antidepressant Use on the Rise as.....

Antidepressant Use on the Rise as Americans Become More Accepting of Psychiatric Medications

Caroline Cassels

Authors and Disclosures

Other Health Care Provider Rating:

August 7, 2009 — A broad and marked increase in antidepressant use is occurring in the United States, with more and younger individuals receiving these medications, new research shows. However, treatment rates remain relatively low among racial and ethnic minorities. A second study suggests Americans have become much more accepting of psychiatric medications — a finding that may partially explain this increase.

In the first study, published in the August issue of the Archives of General Psychiatry, investigators found that the rate of antidepressant use in the United States has almost doubled among Americans older than 6 years — increasing from 5.84% in 1996 to 10.12% in 2005, or from an estimated 13.3 million to 27 million individuals.

Led by Mark Olfson, MD, MPH, from Columbia University Medical Center in New York City, and Steven C. Marcus, PhD, from the University of Pennsylvania in Philadelphia, the study showed there were significant increases in antidepressant use that were evident across all sociodemographic groups examined, except African Americans, who had comparatively low rates of use in both years (3.72% in 1996 and 4.51% in 2005). And they note that although antidepressant treatment increased for Hispanics, it also remained comparatively low in both years (3.72% in 1996 and 5.21% in 2005).

According to the study, antidepressants have recently become the most commonly prescribed class of medications in the United States.

"Several factors may have contributed to this trend, including a broadening in concepts of need for mental-health treatment, campaigns to promote mental healthcare, and growing public acceptance of mental-health treatments," the authors write.

Among antidepressant users, the percentage of individuals who were also prescribed antipsychotic medications increased during the study period — from 5.46% in 1996 to 8.86% in 2005. However, fewer patients received psychotherapy during that time period.

"Together with an increase in the number of antidepressant prescriptions per antidepressant user [an average of 5.6 vs 6.93, respectively, per year], these broad trends suggest that antidepressant treatment is occurring within a clinical context that places greater emphasis on pharmacologic rather than psychologic dimensions of care," the investigators write.

A second study, published in the August issue of Psychiatric Services, examined Americans' opinions about psychiatric medications, and found that they have become increasingly positive over the past decade.

Need for Greater Public Understanding

Although the increase in favorable attitudes is helpful in overcoming a common barrier to treatment, study author Ramin Mojtabai, MD, PhD, from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, notes that the survey results point to a growing challenge for psychiatrists — that of "educating the public and providers to correctly identify conditions that merit the use of psychiatric medications and to distinguish these conditions from self-limited stresses of daily life that do not require medication treatment."

Dr. Mojtabai found that the percentage of individuals willing to take medication for specific psychiatric disorders increased between 1998 and 2006 for depression (from 41% to 49%) and for panic attacks (from 56% to 64%).

In addition, the percentage of individuals willing to take psychiatric medication for conditions not identified with a specific psychiatric disorder increased for trouble in personal life (from 23% to 29%) and to cope with life stress (from 36% to 47%).

"This finding calls for a more targeted and selective approach in public-information campaigns aimed at improving public understanding of the proper uses of psychiatric medications," writes Dr. Mojtabai.

The psychiatric medication questions were part of the US General Social Surveys, face-to-face, biennial, cross-sectional surveys of the general population of the United States conducted by the National Opinion Research Center at the University of Chicago.

Dr. Olfson reports receiving research support from AstraZeneca, PLC, and Ortho-McNeil Janssesn Scientific Affairs LLC. Dr. Mojtabai reports receiving research funding from Bristol-Myers Squibb Pharmaceuticals.

New Review Endorses ....

New Review Endorses CV Benefits of Fish Oil

Lisa Nainggolan

August 10, 2009— A new review concludes that there is extensive evidence from three decades of research that fish oils, or more specifically the omega-3 polyunsaturated fatty acids (PUFAs) contained in them, are beneficial for everyone [1].

This includes healthy people as well as those with heart disease — including postmyocardial infarction (MI) patients and those with heart failure, atherosclerosis, or atrial fibrillation — say Dr Carl J Lavie (Ochsner Medical Center, New Orleans, LA) and colleagues in their paper published online August 3, 2009, in the Journal of the American College of Cardiology.

"We reviewed everything that was published on omega-3 that was clinically important, and the major finding is that there are a tremendous amount of data to support the benefits of omega-3, not just as a nutritional supplement — people have known that for years — but evidence that it prevents and treats many aspects of cardiovascular disease," Lavie told heartwire .

Lavie said he believes physicians are not as familiar with the omega-3 studies as they should be: "Clinicians know the findings of many statin trials even if they do not know all the details — they know that there are a ton of statin data. The omega-3 data may not be as impressive or as plentiful as this, but it should be 'promoted' to clinicians."

Omega-3 PUFA, says Lavie, "is a therapy that clinicians should be considering prescribing to their patients. Not just as something healthy but as something that may actually prevent the next event. In HF [heart failure], it may prevent death or hospitalization and the same thing post-MI." He and his colleagues reiterate the advice of the American Heart Association (AHA): that those with known coronary heart disease (CHD) or HF eat four or five oily-fish meals per week or take the equivalent in omega-3 supplements; healthy people should consume around two fatty-fish meals per week or the same in supplements.

Most Data on EPA and DHA

In their review, Lavie and colleagues explain that most of the data on omega-3 have been obtained in trials using docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the long-chain fatty acids in this family. The most compelling evidence for cardiovascular benefits comes from four controlled trials of almost 40,000 participants randomized to receive EPA with or without DHA in studies of primary prevention, after MI, and most recently with HF, they note.

They discuss the results for each specific cardiovascular condition in turn. For CHF, three large randomized trials — the Diet and Reinfarction Trial (DART), the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI)-Prevenzione, and the Japan EPA Lipid Intervention Study (JELIS) — have indicated that omega-3 PUFAs lower CV risk in both the primary- and secondary-prevention settings, they note.

Lavie elaborated to heartwire : "The benefit is different in different studies but can be as much as 30%." The effects are seen on total mortality, sudden death, CHD mortality, and cardiovascular mortality.

But there are some studies that have not shown favorable results, although there are generally methodological reasons for this, they say. However, they do flag the most recent study of post-MI patients, OMEGA, which suggests there may not be additional short-term benefit of omega-3 PUFAs in low-risk patients already receiving optimal modern therapy.

There is also evidence of benefit in atherosclerosis and in a wide range of arrhythmias, with the most significant effect and potential benefit seen in "the current epidemic" of atrial fibrillation (AF), note the researchers. But more studies are needed to explore the effects of various doses of omega-3 PUFAs on the primary and secondary reduction of AF and to determine whether the benefits are caused by antiarrhythmic effects, benefits on autonomic tone, or even anti-inflammatory effects, they observe.

Benefit of Fish Oils Also Extend to HF

Recently, the potential benefits of omega-3 PUFAs "have been extended to the prevention and treatment of HF," say Lavie et al. Although the reduction in events was "only 8% to 9% in the recent GISSI-HF trial, which is not huge," Lavie admits, "when you think of HF, it's a very serious disorder, and in GISSI-HF, those patients were treated vigorously for their HF, so they were on good therapy, and adding just one [omega-3 PUFA] pill a day reduced deaths by between 8% and 9%, which is a pretty nice additional benefit."

But he and his colleagues say further studies are needed to determine the optimal dosing of omega-3 PUFA for different stages of HFand to investigate the underlying mechanisms for the benefits. However, in the meantime, omega-3 PUFA supplements "should join the short list of evidence-based life-prolonging therapies for HF."

They also discuss the data on omega-3 PUFAs in hyperlipidemia, noting that the FDA has approved one such supplement for the treatment of very high triglyceride levels.

And they note that more studies are needed to determine the optimal mix of DHA relative to EPA in various populations.

Finally, they state that this review does not focus on the plant-based precursor of EPA, alpha-linolenic acid (ALA), which is found in abundance in flaxseed and to a lesser extent in other plants. But they observe "the overall evidence is much weaker for ALA than for EPA and DHA."

Recommendations for Omega-3 Consumption

Mirroring recommendations from the AHA, European Society of Cardiology, and the World Health Organization (WHO), Lavie and colleagues recommend that healthy people consume at least 500 mg per day of EPA/DHA — equal to around two fatty-fish meals per week — and that those with known CHD or HF get 800 to 1000 mg per day EPA/DHA.

Asked by heartwire whether people should try to consume more fish or alternatively take supplements, Lavie says: "If somebody really were eating salmon and tuna and mackerel and sardines, and they were doing that several times a week, then they wouldn't need to be taking a supplement. But in the US, at least, very few people are going to eat the therapeutic doses of fatty fish."

Other good reasons to take supplements include the fact that they have usually had impurities, such as mercury, removed, he notes.

If people are trying to improve their consumption of oily fish, they could take supplements only on the days they were not eating such fish or every other day to try to get up to the recommended amount of omega-3 PUFAs, Lavie says.

But he warns that regimens that are too complex might result in underconsumption: "I would tend to think that most people are getting very little omega-3 PUFAs in the diet. There's no harm in taking extra — the only negative of extra is the calories. I don't think anyone thinks now that fish oil is doing any harm."

Dr. Lavie has been a consultant and speaker for Reliant, Pfizer, Bristol-Myers Squibb, and Sanofi-Aventis and is a speaker receiving honoraria from and on the speaker's bureau of GlaxoSmithKline, Abbott, and Solvay. Disclosures for the coauthors are listed in the article.

Akathisia and Second-generation Antipsychotic Drugs

Akathisia and Second-generation Antipsychotic Drugs

Rajeev Kumar; Perminder S. Sachdev

Authors and Disclosures

Published: 06/02/2009

Abstract and Introduction

Abstract

Purpose of Review: Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.

Recent Findings: Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.

Summary: Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.

Introduction

Second-generation antipsychotics (SGAs), now the mainstay of antipsychotic treatment in most countries, have the shared feature that they produce fewer extrapyramidal side effects (EPSEs) than the conventional or first-generation antipsychotics (FGAs).[1] In fact, this relative lack of EPSEs is considered to be the defining feature of their 'atypicality'.[2] However, SGAs are not free of EPSEs and the whole range of EPSEs generally associated with FGAs has also been associated with the SGAs. In order to better understand the differential rates of EPSE production by the SGAs, a new classification has been suggested based on the dopamine D2 receptor binding affinity concept.[3] In this classification, clozapine and quetiapine are included in the low affinity group, olanzapine in the middle affinity group, and risperidone, ziprasidone, and aripiprazole in the high affinity group. Furthermore, it is suggested that olanzapine and risperidone at higher doses have high D2 occupancy, whereas quetiapine and clozapine do not.

We agree with a recent editorial[4] that the widespread and appropriate attention to metabolic effects with SGAs should not be a reason to ignore the problem of EPSEs, even though they may be mild or less frequent. In this update, we focus on akathisia (from Greek, literally 'not to sit'), one of the most common and disabling side effects of antipsychotics and some other drugs.[5,6] The various forms of akathisia have been well characterized in earlier studies, which include acute, chronic, withdrawal and tardive subtypes.[7,8] Because akathisia differs from Parkinsonian symptoms such as rigidity, bradykinesia, and tremor in its risk factors and treatment response, its pathogenetic mechanisms are also likely to be different, suggesting that drugs that do not produce significant EPSEs may yet cause akathisia. We examine the recent empirical evidence relating akathisia to SGAs and examine the risk factors, pathophysiology, and recent attempts at its treatment.

Previous meta-analyses of randomized double-blind controlled studies[9,10] found that atypical antipsychotics were less likely to produce EPSEs than FGA drugs. As a result of such informative accounts, several clinical guidelines have been developed and recommended that atypical antipsychotics should be used as first-line agents in the treatment of schizophrenia and related disorders.[11] One major criticism of such studies has been the use of high doses of haloperidol as a comparator drug, thus overstating an advantage for atypical over conventional antipsychotic drugs. Rates of akathisia are available from a number of treatment studies using SGA drugs, both in comparison with placebo and with other SGAs and some FGAs

Clozapine

In an older study,[12] clozapine was compared with chlorpromazine in 151 hospitalized patients with schizophrenia. Twelve percent of clozapine patients developed EPSE-related adverse effects compared with 25% in the chlorpromazine group. A later study[13] used the Extrapyramidal Rating Scale (ERS) and extracted the akathisia items from it in 29 patients receiving FGAs and 23 patients receiving clozapine. All patients had a diagnosis of a psychotic disorder. Akathisia was reported to be present in 39% of clozapine-treated patients compared with 45% of patients treated with FGAs. A rare case of acute nocturnal akathisia induced by clozapine has been reported recently in a 43-year-old man with a diagnosis of schizophrenia.[14] The condition was successfully treated with propranolol 40 mg/day while the patient continued 350 mg/day of clozapine. So it is clear that, although clozapine does not increase the risk of Parkinsonism over placebo, akathisia still occurs at a higher frequency. A caveat in relation to clozapine studies is that patients have previously been treated with other antipsychotics and some may have persistent akathisia attributable to the earlier drugs.

Risperidone

In a Cochrane review, it was reported that about 33% of patients with schizophrenia developed EPSEs on risperidone or olanzapine.[15] However, 25% of patients receiving risperidone required medication to alleviate the akathisia, which was significantly higher than those receiving olanzapine during a 12-week to 12-month trial period. The average dose of risperidone ranged from 1.5 to 10 mg/day and from 5 to 30 mg/day for olanzapine. The generally recommended dose for risperidone (up to 6 mg/day) is much less than the upper range of 10 mg/day, with the drug losing its EPSE advantage at the higher doses. A similar rate of 27.5% EPSEs was reported in another review in comparison with 12.8% of placebo-treated patients with autism spectrum disorders.[16] A review based on published studies on the safety and efficacy of risperidone augmentation of clozapine in clozapine treatment-resistant patients showed that 9.3% of patients reported EPSEs or akathisia.[17] The low rate of akathisia could be attributed to the use of low-dose risperidone.

Olanzapine

A pooled analysis of four randomized open-label studies in the Middle East and North Africa on olanzapine versus chlorpromazine in the treatment of schizophrenia was reported recently.[18] The dose ranged from 5 to 20 mg/day for olanzapine (n = 83) and from 200 to 800 mg/day for chlorpromazine (n = 40). Akathisia was reported in 2.4% of the olanzapine group compared with 10% in the chlorpromazine group. The European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study[19] reported the effectiveness and tolerability of olanzapine monotherapy and olanzapine combination therapy with other antipsychotics, anticonvulsants, and/or lithium in the treatment of mania after a 12-week trial. The incidence of akathisia was 3% in the olanzapine monotherapy group compared with 6% in the olanzapine combination group, a statistically significant difference.

Quetiapine

Prevalence of EPSEs and akathisia in quetiapine-treated bipolar manic patients has been reported based on four randomized placebo-controlled double-blind trials.[20] Studies evaluated quetiapine monotherapy (800 mg/day), versus placebo, with lithium or haloperidol monotherapy as controls, quetiapine in combination with a mood stabilizer (lithium or divalproex) compared with placebo and a mood stabilizer. Studies used the Simpson-Angus Scale (SAS) and Barnes Akathisia Scale (BAS) for assessment of EPSEs and akathisia, respectively. There was no difference in the incidence of EPSEs between quetiapine monotherapy and placebo (12.9 versus 13.1%), quetiapine in combination with lithium/divalproex and placebo in combination with lithium/divalproex (21.4 versus 19.2%). The incidence of akathisia was 3.3% with quetiapine monotherapy compared with 6.1% with placebo. Even the combination of quetiapine with lithium/valproex showed an incidence of only 3.6% compared with 4.9% with placebo and lithium/divalproex combination. The study concluded that quetiapine treatment was similar to placebo in terms of the occurrence of akathisia in bipolar patients. In a study of switching from previous antipsychotics to quetiapine in patients with schizophrenia and preexisting EPSEs,[21] the authors noted a significant reduction in Parkinsonism and akathisia

Iloperidone and Ziprasidone

A large 4-week, randomized, placebo-controlled, multicentre study comparing the efficacy and safety of iloperidone with ziprasidone and placebo[22] showed that iloperidone was associated with lower incidence of EPSEs, particularly akathisia compared with ziprasidone. These findings suggest that drugs such as iloperidone with mixed D2/5-HT-2 antagonism may be superior to other SGAs in terms of their EPSE profile. Sudden emergence of akathisia following ziprasidone dose reduction has been reported in four female patients with bipolar disorder, alerting the clinicians that SGAs may be associated with sudden EPSEs while they are taking or discontinuing their drugs.[23] Although withdrawal akathisia has been reported with FGAs, controlled studies are lacking with SGAs.

Aripiprazole

The efficacy and safety of aripiprazole as an adjunct therapy in major depressive disorder showed that akathisia occurred in 4.5% of those patients who took an antidepressant and an adjunct placebo, compared with 23.1% of those who took an antidepressant and adjunct aripiprazole,[24] although only one patient discontinued due to akathisia. A Cochrane systematic review of aripiprazole versus FGAs showed that aripiprazole was superior to typical antipsychotics in terms of occurrences of EPSEs and tolerability.[25] The relative risk (RR) of akathisia in 897 patients from three randomized controlled trials was calculated as RR 0.39 [confidence interval (CI) 0.3-0.6], number needed to treat (NNT) 11 (CI 14-9). In an open-label, rater-blinded, aripiprazole augmentation study on treatment-resistant depression,[26] akathisia was reported in 20% of patients, suggesting that antidepressants in combination with FGAs may increase the incidence of akathisia. Another study using aripirazole in refractory bipolar depression[27] found that 42% of patients had treatment-related akathisia, again suggesting that SGAs in combination with other psychotropic medications will increase the risk of development of akathisia.

Amisulpride

The effectiveness and tolerability of amisulpride was compared with that of risperidone for the treatment of behavioural and psychological symptoms in patients with Alzheimer's disease.[28] EPSEs were reported to be 20% in the amisulpride group compared with 38.4% in the risperidone treatment group. The average dose for amisulpride was 85 mg/day and for risperidone 1.8 mg. There was no statistically significant difference between amisulpride and risperidone in terms of the occurrence of akathisia as measured by BAS (0.3 ± 0.5 versus 0.2 ± 0.4). It is worth noting that the study used very low doses of risperidone and amisulpride.

Naturalistic and Large Studies Using Several Second-generation Antipsychotics and Low Potency First-generation Antipsychotics

FGAs were compared with SGAs in a naturalistic setting in Finland.[29] The authors studied 100 patients with psychosis who were attending a polyclinic. Akathisia was rated using BAS and antipsychotic doses were converted to chlorpromazine equivalents. A total of 17 patients (17%) were detected to have akathisia. Of particular importance is that none of the patients in the SGA groups had akathisia. In the FGA groups, the prevalence of akathisia was marked with the highest rate of 44% in the depot FGAs and selective serotonin reuptake inhibitor (SSRI) group. Unfortunately, the names of individual FGAs or SGAs were not provided in this study. Additionally, the conversion of drug doses to chlorpromazine equivalents can be questioned for its accuracy.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study is a major advance in the study of efficacy and tolerability of antipsychotics in a real-life clinical setting. An earlier report on this study showed no difference in the prevalence of drug-induced Parkinsonism, akathisia, or any abnormal movements in patients receiving olanzapine, quetiapine, risperidone, ziprasidone, or perphenazine.[30] However, it did show that akathisia still was a problem and occurred at a frequency of 5% in patients treated with olanzapine or quetiapine, 7% for risperidone or perphenazine, and 9% for ziprasidone. The comparable rates of akathisia with perphenazine and SGAs could be related to a sampling bias in the CATIE study, in which patients with tardive dyskinesia were not included in the perphenazine group. A subsequent more rigorous analysis of the CATIE data also showed that the incidence of treatment emergent Parkinsonism, akathisia, and tardive dyskinesia was not significantly different between moderate dosages of perphenazine (an intermediate potency conventional antipsychotic) and the four newer forms of atypical antipsychotics.[31] However, it is worth noting that there was a trend towards more patients on risperidone and perphenazine receiving medications for treatment of akathisia. In a recent double-blind comparison study of FGAs and SGAs (Treatment of Early Onset Schizophrenia Spectrum Disorders - TEOS study),[32] researchers compared the efficacy and safety of olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day), and 1 mg/day of benztropine for 8 weeks. The adverse effects profile of these drugs showed that 18% of patients on molindone, 13% on olanzapine, and around 8% on risperidone had akathisia rated using the BAS.

The differential effects of EPSEs with SGAs were studied in patients with bipolar disorders.[33] The authors classified the SGAs into low potency (quetiapine, olanzapine) and high potency (risperidone, ziprasidone, aripiprazole) groups. They assessed 51 individual patient trials for a mean duration of 25.5 weeks. EPSEs were assessed using the Abnormal Involuntary Movements Scale (AIMS), BAS, and SAS. Results showed that 62.7% of trials resulted in moderate-to-severe EPSEs. There were no differences between high and low-potency agents in terms of EPSE frequencies or discontinuation rates. However, in a multiple regression model, akathisia was found to be less common in low-potency drugs. In addition, patients in the younger age group were more likely to have akathisia. This important study highlights the fact that EPSEs occur at a higher frequency than reported by clinical trials.

Longitudinal studies focusing on akathisia, both for its longitudinal course and delayed or tardive onset with SGAs, are generally lacking. In a recent longitudinal study, Modestin et al.[34] reported an interesting trend of akathisia occurring at a rate of 14% during both their baseline assessment in 1995 and follow-up in 2003/04. However, they noted that patients who took clozapine improved remarkably, whereas the condition of patients on other atypicals (olanzapine, risperidone, quetiapine, and sertindole) became worse. Although there are methodological issues in interpreting the results, the study underscores the fact that atypical antipsychotics continue to produce significant akathisia during long-term use, with the likelihood that although some patients improve, others develop akathisia with a delayed onset. A number of methodological issues need to be considered in studies that assess akathisia. First, comparing EPSE rates from different trials cannot adequately account for population (e.g. age, sex, diagnosis, ethnicity, etc.) and methodological differences. Pooling data from multiple studies can further complicate this issue. Second, most studies are designed to have adequate power to detect clinical effectiveness rather than side effects, thus creating underpowered studies for the evaluation of side effects. Third, akathisia can often be mistaken for agitation related to the underlying psychiatric disorder, thereby creating an underreporting bias. It is known that akathisia can be intermittent or have a delayed onset, thereby missing the diagnosis during office visits or in short duration trials. Finally, randomized controlled trials do not usually reflect real-life clinical settings. Patients enrolled in the studies are highly selected and patients with various risk factors that can potentially increase the risk of EPSEs are often excluded.

Risk Factors

We systematically looked at the recently published studies related to risk factors for SGA-induced akathisia. In a systematic review conducted by Gao et al.[35] of studies on the frequency of occurrence of EPSEs induced by antipsychotics in patients with bipolar disorder and schizophrenia, it was concluded that bipolar-depressed patients are at increased risk of acute antipsychotic-induced movement disorders. The authors used number needed to harm (NNTH) to estimate the risk. In regard to akathisia, the NNTH was 7 for haloperidol in patients with schizophrenia compared with 17 for aripiprazole, 19 for olanzapine, 17 for quetiapine, and 35 for ziprasidone. In mania, the NNTH in relation to akathisia was 4 for haloperidol and 9 for aripiprazole, both suggesting an increased risk. However, the NNTH for quetiapine and ziprasidone was much higher. Of particular note was that a NNTH of 5 was observed for aripiprazole in patients with bipolar depression. These findings suggest that patients with bipolar mood disorders, in particular bipolar depression, are at increased risk of developing akathisia with both conventional and atypical antipsychotics. These findings are relevant because several atypical antipsychotics are currently used for the treatment of bipolar disorders.

Patients in palliative care units may develop several neuropsychiatric syndromes that include delirium, agitation, and other behavioural disturbances due to various types of neurological and neuropsychiatric conditions. In addition, they also develop nausea and other general medical disturbances. Clinicians use a number of medications in the palliative care setting, which include antiemetics (metoclopramide, prochlorperazine), antipsychotics, antidepressants (tricyclics, SSRIs) and calcium channel blockers (cinnarizine, flunarizine, diltiazem), all of which can cause significant akathisia.[36] If the akathisic symptoms are misdiagnosed in these settings, patients might be further treated for agitation and subsequently be prescribed antipsychotics, which would further aggravate akathisia. An association between akathisia and acculturation has been reported in an Australian study,[37] in which the authors found a 60% prevalence of akathisia in a community sample of patients treated with olanzapine, risperidone, fluphenazine, zuclopenthixol, trifluperazine, and haloperidol. The association between smoking and akathisia was reported in a recent study.[38] The authors explored the self-medication hypothesis, whereby smoking would reduce akathisia in a sample of 250 outpatients with schizophrenia. Using the BAS, the authors noted that heavy smoking was not associated with akathisia (41% of patients with akathisia were heavy smokers versus 39% of patients without akathisia), arguing against the hypothesis. Psychoactive substances may interact with antipsychotics causing EPSEs or worsening of EPSEs. The results so far have been inconsistent and this may be partly due to methodological limitations. In a recent study, Potvin et al.[39] addressed this issue by investigating the effects of psychoactive substances on EPSEs in a sample of 41 patients with dual diagnosis schizophrenia. All patients were treated either with clozapine or quetiapine for at least 4 weeks. EPSE instruments used were the Extrapyramidal Symptoms Rating Scale (ESRS) and the BAS. In this well controlled study, patients with dual diagnosis were more likely to show higher scores on subjective EPSE complaints and higher ESRS scores than the schizophrenia only group. Of note, patients with a dual diagnosis had more Parkinsonian signs, and a subgroup analysis showed that patients abusing cocaine had more EPSE complaints, EPSEs, Parkinsonism, and signs of akathisia. As this was a cross-sectional study, one cannot determine the directionality of the cause and effect

The Subjective Experience of Akathisia

Some recent studies have looked at the subjective experience of akathisia. Sixty-seven outpatients with schizophrenia treated with risperidone or haloperidol were assessed for akathisia (BAS) and their subjective cognitive dysfunction (Frankfurt Compliant questionnaire).[40] The results showed that akathisia was significantly correlated with a number of subjective cognitive-perceptual deficits. These included anxiety, disorder of selective attention, perceptual disorder, and disorder of coping responses. The authors highlighted the importance of early therapeutic interventions for akathisia to reduce subjective cognitive dysfunction and impairment of coping. The subjective experience of akathisia was further highlighted in a series of four cases reported recently.[41] The author emphasized that side effects such as akathisia can be misinterpreted by the patients and adequate attention should be paid to the patients' experiences and supportive as well as cognitive behaviour therapy should be used to reduce such experiences. It has also been noted that akathisia occurring early in treatment or after increases in doses may be more troublesome and distressing for the patents.[42] Chronic akathisia from risperidone has been reported recently as a reason for a patient to become extremely irritable, easily agitated, and sometimes violent.[43]

Second-generation Antipsychotic-induced Akathisia in Children and Adolescents

In a large naturalistic sample of adolescent patients with schizophrenia treated predominantly with SGAs, Gebhardt et al.[44] reported that akathisia assessed by BAS significantly correlated with the subscale items of hostility and suspiciousness suggesting that movement disorders and psychopathology may have shared anatomical/pathophysiological mechanisms. However, this may be related to problems in the diagnosis of akathisia and distinguishing it from other symptoms. In an open-label, randomized comparison of olanzapine versus risperidone in the treatment of childhood onset schizophrenia, 25 children were assessed for efficacy and tolerability.[45] The average dose range for risperidone was 0.25-4.5 mg/day and 2.5-20 mg/day for olanzapine. Akathisia assessed by the BAS was not significantly different in the two groups, suggesting that the two drugs did not differ in terms of their EPSEs in children with schizophrenia.

Pathophysiology of Akathisia

Although there are many possible hypotheses for the pathophysiology of acute akathisia, none is completely satisfactory. So far the most attractive hypothesis is dopamine receptor blockade in the mesocortical and mesolimbic regions of the brain. It is unlikely that a single neurotransmitter hypothesis will explain all the complex features of the disorder, and the interaction of several neurotransmitters may be involved. There have been some recent imaging, genetic, and neurotransmitter depletion studies that have looked at the pathophysiology of akathisia. Striatal dopamine-2 (D2) receptor occupancy by antipsychotics has been implicated in the pathophysiology of EPSEs. In this regard, a recent study using single photon emission computed tomography (SPECT) and ligand iodobenzamide showed that bipolar patients receiving 5-45 mg/day of olanzapine for 2 weeks did not show any EPSEs at a D2 occupancy level of 28-80%, suggesting that, at clinically relevant doses, it is unlikely that bipolar patients would develop EPSEs.[46] In a recent study,[47] dopamine depletion using the administration of alphamethyl paratyrosine (AMPT) resulted in subjective changes in a group of patients with schizophrenia, including dysphoria, social withdrawal, and personal distress followed by akathisia, akinesia, and rigidity.

In a single case study,[48] olanzapine-induced akathisia was studied using 18F-fluoro-deoxyglucose-positron emission tomography (FDG-PET) during akathisia and after recovery. Results showed that akathisia was associated with reduced metabolic activity in the thalamus and cerebellum. More importantly, the metabolic activity recovered when akathisia disappeared after discontinuation of olanzapine. The role of the serotonin system was also explored in a study on the role of serotonin transporter promoter genotypes in acute antipsychotic efficacy and side effects in schizophrenia.[49] The authors used the SAS, BAS, and abnormal involuntary movement scale for assessment of EPSEs. There was no significant association between EPSEs and the serotonin transporter promoter gene polymorphism.

Treatment

Although there has not been any major advance in the treatment of SGA-induced akathisia, all akathisia treatment trials are relevant, as the findings may be applicable to SGA-induced akathisia. So far the established treatments for neuroleptic-induced akathisia include anticholinergic and antiadrenergic drugs in addition to a dose reduction strategy if possible. A recent Cochrane review on the evidence of anticholinergics in neuroleptic-induced akathisia concluded that there was insufficient data based on good quality research to support the use of anticholinergics.[50] However, we suggest that anticholinergics should not be abandoned in the treatment of akathisia.[6] One randomized trial of multiple doses of diphenhydramine as a prophylactic agent in metoclopramide-induced akathisia in an emergency setting has been reported.[51] The results of the trial indicated that there was no advantage of routine prophylactic use of diphenhydramine, but for patients who took 20 mg of metoclopramide, less subjective restlessness was reported. The role of mirtazapine in the treatment of akathisia was reviewed recently based on a limited number of publications.[52] So far there have been three case reports, one placebo-controlled trial, and one placebo and propranolol-controlled study. Pooled results showed that mirtazapine demonstrated an overall response rate of 53.8% compared with a 7.7% response rate for placebo and a 30% response rate for propranolol. One of the above studies was a randomized, double-blind, placebo-controlled and propranolol-controlled study, which needs some attention.[53] Ninety patients with antipsychotic-induced akathisia were randomly assigned to mirtazapine, (n = 30, dose 15 mg/day), propranolol (n = 30, dose 80 mg/day), or placebo (n = 30). A reduction of two points on the BAS was used as the primary outcome measure. Twenty-six percent of patients dropped out due to lack of response or adverse events. A reduction in the BAS score was found in 34% of patients in the mirtazapine group and in 29% of those in the propranolol group compared with placebo, which showed a reduction in 11%. Forty-three percent of patients in the mirtazapine-treated group and 30% in the propranolol-treated group responded to treatment compared with 6.7% in the placebo group. Five patents from the propranolol group dropped out due to hypotension or bradycardia compared with none in the mirtazapine group. The authors concluded that mirtazapine should be considered as a first-line treatment option for acute antipsychotic-induced akathisia, especially when propranolol is contraindicated in some patients. However, it is important to keep in mind that antidepressant medications, including mirtazapine, have been implicated in the genesis of akathisia. Another interesting trial compared the efficacy of intramuscular biperiden with isotonic saline in a double-blind randomized design[54] and noted that intramuscular biperiden had no advantage over isotonic saline in treating acute neuroleptic-induced akathisia. On the basis of the above trials, no firm conclusions can be drawn. Perhaps, the best approach now is to follow previously established clinical practice in the management of acute akathisia, which includes dose reduction and the use of drugs such as anticholinergics, antiadrenergic drugs, mianserin or ritanserin, and possibly mirtazapine. A case of aripiprazole-induced tardive akathisia responding to the dopamine agonist ropinirole has been reported recently.[

Conclusion

There is clear evidence that akathisia is a side effect of SGAs, though less frequently than with the conventional antipsychotics. The presence of akathisia can lead to noncompliance, personal distress, and increased suicide risk for the patients. Along with management of other side effects of SGAs, such as the metabolic syndrome, adequate attention should be paid to EPSEs, in particular akathisia.

Current Research in Treatment-resistant Depression....

Current Research in Treatment-resistant Depression: When to Augment and When to Switch: Introduction and Switching Strategies for Treatment-resistant Depression

Authors and Disclosures

Introduction

The goal of antidepressant drug therapy should be the absence of significant depressive symptoms along with a complete recovery of social and vocational function, referred to as full remission.[1] With any first-choice antidepressant medication, about 50% to 70% of patients will have a significant treatment response (usually defined as a 50% or greater decrease in depressive symptoms). Of these treatment responders, however, only about one half to one third attain a full remission. Hence, a significant proportion of depressed patients are left with residual or persistent symptoms despite apparently adequate antidepressant therapy. Treatment-resistant depression (TRD) is therefore defined as the failure to achieve full remission with an antidepressant drug used at an adequate dose for an adequate duration of time.[2] When patients have not had a satisfactory response despite optimal treatment, the 2 basic treatment strategies are switching to an alternative antidepressant therapy or adding a second antidepressant therapy.[3,4] The failure to achieve remission with antidepressant therapy is associated with an increased risk for relapse or recurrence, higher levels of impaired social and vocational function, and a worse long-term prognosis. A significant minority of patients having chronic TRD (about 20% to 30%) do not have a satisfactory response to sequential trials of various drug-drug and drug-psychotherapy combinations.[1] Chronic TRD is associated with persistent social and vocational disability, an increased risk for suicide, greater medical morbidity and mortality, and higher healthcare utilization and costs.[5-7] In this article, I will review various treatment approaches for TRD, but will emphasize combination and augmentation strategies.

Switching Strategies for Treatment-resistant Depression

Switching to an alternative antidepressant drug is generally recommended for patients who have shown minimal or no response at all to the first antidepressant, or for those who have intolerable side effects, because adding a second medication is unlikely to be more effective or better tolerated than trying the second medication alone.[3]The serotonin reuptake inhibitor (SRI) drugs are the most commonly used class of antidepressants, and they are often the first-choice treatment. Although these drugs have a similar mechanism of action, individual patient response to different medications within the class of SRI drugs may vary considerably because these drugs are chemically dissimilar. Patients not responding to 1 SRI therefore may be appropriately switched to a second alternative SRI. Patients not responding after 2 adequate SRI trials, however, generally should be switched to an alternative antidepressant from another class. The older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are available, but are not commonly used because of their adverse side effect and safety profiles. These drugs can be effective for TRD, however.[8,9] A transdermal formulation of the MAOI selegiline, which is safer and better tolerated than older MAOI drugs, may be a more popular MAOI treatment option for TRD, although it has not been formally studied in these types of patients.[10

^{Combination and Augmentation Strategies for Treatment-resistant Depression}

Combination therapy typically refers to the combined use of 2 US Food and Drug Administration (FDA)-approved antidepressant drugs, whereas augmentation refers to the addition of a second non-antidepressant agent to an antidepressant drug. Adding a second medication to the primary antidepressant drug may be most useful in patients who have shown at least a partial response to the antidepressant, because of the potential additive or synergistic effects.[11] Combining different medications should also be considered for patients who have not responded to multiple monotherapy trials using antidepressants from several different classes. Although the response to combination or augmentation may sometimes occur rapidly at an initial dose of the second medication, it is still important to optimize the dose and duration of each treatment when they are used together.

Combining Antidepressant Drugs

With the exception of MAOI drugs, combining 2 or more antidepressant drugs usually can be safely done. Combinations with TCAs and other antidepressants have been described in the literature, but virtually all reports are based on uncontrolled studies. The effectiveness of various antidepressant combinations for TRD has not been well studied or clearly established.[12] Combining an SRI drug with bupropion or mirtazapine is a common although not thoroughly investigated, strategy.

Combination with bupropion is a popular strategy, but its efficacy for TRD has not been systematically studied.[13]In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the efficacy and tolerability of various antidepressant therapies were evaluated through 4 sequential treatment steps.[14] In the medication augmentation arm of the second level of STAR*D, nonremitters to citalopram were randomized to receive augmentation with bupropion or buspirone.[15] The bupropion and buspirone groups had similar rates of remission and response. Bupropion, however, was associated with a significantly greater reduction in depression scores (from baseline to the end of level 2) than was buspirone, and it was associated with a significantly lower dropout rate due to intolerance than was buspirone.

Because of its unique pharmacology, mirtazapine combination is another approach. In a randomized controlled trial, patients who had failed to respond to at least 4 weeks of monotherapy with a newer generation antidepressant drug (an SRI, venlafaxine, or bupropion) continued to take the ineffective drug and were randomly assigned to receive four weeks of augmentation with either mirtazapine or placebo.[16] Response rates for mirtazapine augmentation (63.6%) were significantly better than those for placebo (20.0%). When 9 placebo nonresponders were treated openly with mirtazapine at the end of the study, 5 patients (55.5%) remitted. For the last level of STAR*D, nonremitters after the first 3 treatment steps were randomly assigned to switch to tranylcypromine or to venlafaxine/mirtazapine combination.[17] Remission rates were lower for tranylcypromine compared to venlafaxine/mirtazapine, although the difference was not statistically significant. Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance than was the combination.

Augmentation With Mood Stabilizer Drugs

Lithium is an FDA-approved mood stabilizer treatment for bipolar disorder. Based on randomized placebo-controlled studies, lithium is the most extensively studied and best established augmentation strategy for TRD.[18]It is not commonly used in contemporary clinical practice because of its perceived adverse side effects and safety.[19] When used, it is most effective at a dose that achieves a blood level of 0.8 mEq/L or greater.[20] In the augmentation arm of the third level of STAR*D, nonremitters after 2 treatment steps were randomly assigned to augmentation with lithium or thyroid hormone (triiodothyronine; T3).[21] Remission rates were lower for lithium compared to T3, but the difference was not statistically significant. Lithium was more frequently associated with side effects, and more patients taking lithium left treatment because of side effects.

Anticonvulsant drugs are FDA-approved for the treatment of seizure disorders. Many are commonly used as mood-stabilizing drugs for the treatment of bipolar disorder, and valproic acid, carbamazepine, and lamotrigine are FDA-approved for this indication. Anticonvulsants typically have relatively better antimanic effects than antidepressant effects, but lamotrigine is somewhat unusual in having relatively better antidepressant effects.[22] Lamotrigine decreases the release of the excitatory amino acid glutamate, and it also has modest blocking effects on the reuptake of serotonin and dopamine. Several open-label studies found it effective for unipolar TRD.[23,24] A small placebo-controlled study did not demonstrate significant benefit for lamotrigine augmentation in TRD on the primary outcome measure, but it was significantly more effective than placebo on several secondary outcome measures.[25] In an open-label randomized study, lamotrigine and lithium augmentation were similarly effective.[26]Carbamazepine has a main chemical structure similar to TCA drugs. It was found to have significant antidepressant effects in a unipolar treatment-naïve patient group.[27] In an open-label randomized study, carbamazepine and lithium augmentation were similarly effective for TRD.[28]

As a class, the pharmacology of second-generation (atypical) antipsychotic drugs (SGAs) is very complicated. Because of their dopamine-2 receptor blocking effects, SGAs are classified as antipsychotic drugs and are all FDA-approved for the treatment of schizophrenia. The SGAs have significantly greater effects on blocking serotonin-2 receptors compared to first-generation (typical) antipsychotic drugs (FGAs), and SGAs have effects on other neurotransmitters and their receptors.[29] These pharmacologic effects vary among each of the SGA drugs. The constellation of these pharmacologic properties has 2 important clinical implications. First, SGA drugs are generally less likely to be associated with Parkinsonian effects compared to FGA drugs. Second, many of the SGAs appear to have antidepressant effects. FGA and SGA drugs are effective for the acute treatment of mania. However, the additional antidepressant effect of SGA drugs contributes to their overall mood stabilizing qualities.

The investigation of SGA drugs to augment antidepressants for unipolar TRD in randomized placebo-controlled trials has increased considerably in recent years.[29] With the exception of lithium, these drugs are now the best studied augmentation agents for TRD. Aripiprazole is FDA-approved as an add-on therapy (together with another antidepressant drug) for TRD.[30] The proprietary combination of fluoxetine and olanzapine (olanzapine-fluoxetine combination) is FDA-approved for TRD.[31] Risperidone[29,32] and quetiapine[33,34] have also been shown to be effective for TRD, but are not FDA-approved for this indication. Ziprasidone has not been as well studied for TRD.[35,36]

Augmentation With Endocrine Hormone Drugs

The antidepressant use of thyroid hormone is based on the known association between depression and hypothyroidism, as well as on evidence that the hypothalamic-pituitary-thyroid axis is important for neuronal function and neurotransmission in the brain.[37] Thyroid augmentation has been studied almost exclusively in TCA nonresponders, and these studies have suggested that it may be more effective in women, perhaps because of their higher risk for thyroid disease.[38] Thyroid hormone augmentation has been less well studied than lithium or SGA augmentation, but better studied than other combination and augmentation strategies. T3 is easier to use and has been better studied than thyroxine. In a placebo-controlled comparison, T3 and lithium augmentation were similarly effective for TCA TRD.[39] However, as described above, T3 was somewhat more effective and better tolerated than lithium in the level 3 augmentation arm of STAR*D.[21]

Abnormal regulation of the hypothalamic-pituitary-adrenal axis, leading to persistent elevations in cortisol levels, has been implicated in the pathophysiology of depression.[40] A number of open-label and controlled studies of drugs that suppress or inhibit hypothalamic-pituitary-adrenal axis function, such as dexamethasone, aminoglutethimide, metyrapone, ketoconazole, and mifepristone, have shown some benefit for the treatment of major depression, including TRD.[41-47]

Several lines of evidence have suggested an important role for gonadal and adrenal steroid hormones in mood regulation. Women are especially vulnerable to mood disturbances during premenstrual, postpartum, and perimenopausal periods.[48] There also is evidence that mood disturbances may be associated with decreased steroid hormone levels in men.[49] In addition, steroid hormones act on specific receptors in the brain and affect neuronal function and neurotransmission. Considerable evidence suggests that estrogen may improve mild mood symptoms in perimenopausal women, but there is less consistent evidence that estrogen or estradiol are effective as monotherapy for clinical depressive syndromes.[50-52] There also is inconsistent evidence of the antidepressant effects of testosterone in men.[53,54] A small placebo-controlled study found that estrogen augmentation of antidepressants was effective for perimenopausal women with TRD.[50] Several placebo-controlled studies of testosterone augmentation in men with TRD had mixed results, although the sample sizes of the studies were small.[55] The adrenal steroid hormone dehydroepiandrosterone, which is precursor to testosterone and estrogen, has a significant role in mood regulation.[56] A small placebo-controlled study suggested benefit with dehydroepiandrosterone augmentation for TRD.[57]

Augmentation With Miscellaneous Drugs

Buspirone is a nonbenzodiazepine drug indicated for the treatment of generalized anxiety disorder. It is a partial agonist at post-synaptic serotonin-1A type receptors, modulating serotonin release, and has antidepressant properties at higher doses (eg, up to 60-90 mg/day). Some controlled studies have found buspirone augmentation to be effective in TRD.[58,59]

As described above, buspirone was somewhat less effective and less well tolerated compared to bupropion in the augmentation arm of the second level of STAR*D.[15]

Atomoxetine is a selective norepinephrine reuptake inhibitor antidepressant drug. It has relatively weak antidepressant effects, but is FDA-approved for the treatment of attention-deficit/hyperactivity disorder. A placebo-controlled study of atomoxetine augmentation for TRD found no benefit,[60] although the drug might be useful for treating fatigue associated with depression.[61]

Modafinil has a stimulating effect in the central nervous system, possibly by activating α-adrenergic and dopamine activity in discrete regions of the brain, but the effect is unlike that of methylphenidate or amphetamine. It is FDA-approved for the treatment of narcolepsy and excessive daytime sleepiness associated with sleep apnea. It is used as alternative treatment for attention-deficit/hyperactivity disorder, and is added to antidepressant drugs (typically SRIs) to augment their clinical effects and to treat certain adverse effects (eg, apathy, fatigue, and sexual dysfunction). A pooled analysis of 2 placebo-controlled augmentation studies found it modestly effective for improving depression, sleepiness, and fatigue.[62]

Pindolol is a β-adrenergic blocking drug with intrinsic sympathomimetic activity. Under conditions of increased adrenergic activity, it blocks postsynaptic β-1 and β-2 receptors. When basal levels of adrenergic activity are lower, however, it has weak partial agonist effects on these receptors. Pindolol also blocks presynaptic 5-HT1A receptors, an effect that increases the presynaptic release of serotonin from neurons. Based on these unique effects on adrenergic and serotonergic activity, pindolol has been used successfully to augment and accelerate the therapeutic effects of antidepressant drugs, although most controlled studies have not shown it to be very effective for TRD.[63]

Glutamate is the major excitatory neurotransmitter in the brain. Glutamate systems have been directly or indirectly implicated in mood disorders and other neuropsychiatric conditions. Glutamate receptor systems are very complex, and they can be segregated into various distinct receptor subtypes according to their molecular and pharmacologic properties.[64] The two main classes of glutamate receptors are referred to as "ionotropic" and "metabotropic." Ionotropic glutamate receptors are classified into 3 groups: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid , and kainate.

NMDA receptor antagonist drugs have antidepressant effects in animal models of depression. Ketamine, an anesthetic agent derived from the hallucinogenic drug phencyclidine, is a high-affinity NMDA receptor antagonist. In a double-blind crossover study of 18 patients with TRD, 2 doses of intravenous ketamine (at subanesthetic doses) or placebo were given 1 week apart.[65] Compared to placebo, ketamine was more rapidly and significantly effective in improving depressive symptoms. However, ketamine was also more likely to cause perceptual disturbances, confusion, and euphoria, which may be because it binds to an NMDA site that is closely associated with the phencyclidine binding site. Hence, the antidepressant usefulness of ketamine is limited due to potentially serious adverse effects, but this study confirms that NMDA antagonism has antidepressant effects.

The anticonvulsant lamotrigine, an approved treatment for bipolar disorder, decreases glutamate release. In a controlled study of nondepressed normal subjects given subanesthetic doses of ketamine, lamotrigine plus ketamine significantly decreased (compared to placebo plus ketamine) the perceptual disturbances associated with ketamine and significantly increased the immediate mood-elevating effects of ketamine.[66] However, a recent controlled study did not demonstrate that pretreatment with lamotrigine was more effective than placebo in attenuating the neuropsychiatric side effects of ketamine in patients with TRD.[67]

Riluzole is an approved treatment for amyotrophic lateral sclerosis. It inhibits the release of glutamate, but it also may have indirect effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptors and may increase the reuptake of glutamate. Several open-label studies have suggested that it may be effective and well tolerated in patients with TRD[68,69] and bipolar depression,[70] but no controlled studies have been reported. In a controlled study, riluzole was not significantly better than placebo for preventing relapse among a group of ketamine-responsive patients with TRD.[67]

Memantine is an approved treatment for Alzheimer's disease.[71] Compared to ketamine, memantine is a low-affinity NMDA receptor antagonist that is not associated with serious adverse neuropsychiatric effects.[72] A double-blind placebo-controlled study[73] of patients with major depression did not show that memantine was effective and it has not been studied in TRD.

In 1972, Janowsky and colleagues[74] hypothesized that the cholinergic system plays a central role in the pathogenesis of mood disorders. In a recent investigation of the potential antidepressant effects of the anticholinergic drug scopolamine, Furey and Drevets[75] reported on the results of 2 studies: an initial double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Among the 18 depressed outpatients, 12 were chronically depressed and 5 had TRD. Significant reductions in depression and anxiety ratings were observed after the administration of scopolamine compared to their baseline and compared with placebo. These scopolamine effects persisted when subjects switched to the placebo sessions. Patients acutely experienced elevations in confusion during scopolamine administration, but it was otherwise well tolerated.

Psychotherapy for Treatment-resistant Depression

Various short-term structured forms of psychotherapy have been developed specifically for treating depression.[76]These depression-focused psychotherapies include intensive short-term dynamic psychotherapy , interpersonal psychotherapy, various behavioral therapies, and cognitive behavioral therapy (CBT). Cognitive behavioral analysis system of psychotherapy is a modified form of CBT that incorporates some principles of interpersonal psychotherapy. Although combining pharmacotherapy and psychotherapy is commonly recommended in clinical practice, there is no clear evidence that the combination is more effective than either modality alone in the treatment of uncomplicated depressions. Combining psychotherapy and pharmacotherapy is more beneficial for treating and managing complicated depressions, such as chronic depression or TRD.[77,78] A number of reports have described the use of short-term dynamic psychotherapy,[79] interpersonal psychotherapy,[80] CBT,[81-83]behavioral therapy,[84] and cognitive behavioral analysis system of psychotherapy[85] for TRD.

In the second level of STAR*D, CBT was compared with medication augmentation and switch strategies for nonremitters to citalopram.[87] Patients were randomly assigned to augmentation (citalopram with CBT or with medication) or to switch (to CBT or to another antidepressant). Patients who received CBT (either alone or in combination with citalopram) had similar response and remission rates compared with those assigned to medication-only strategies. For patients who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with CBT. Among those who discontinued citalopram (switching to CBT or to medication), there were no significant differences in outcome, although patients who switched to a different antidepressant reported significantly more side effects than patients who received CBT alone.

Neurostimulation Therapies

The oldest and most commonly known form of neurostimulation is electroconvulsive therapy (ECT). It has been shown to be highly effective for the treatment of TRD.[87] ECT involves the passage of a brief electrical current through the brain to induce a generalized seizure lasting about 30 to 90 seconds. A typical course of ECT consists of 6 to 12 treatments given 3 times weekly, although patients with TRD might require a greater number of treatments. One of 2 electrode placements is used for ECT: unilateral nondominant hemisphere placement or bilateral placement. Most patients are treated initially with unilateral ECT. Bilateral ECT usually is reserved for patients who have shown a minimal response after 6 unilateral treatments, or for patients with a history of a poor response to prior courses of unilateral ECT, a history of a positive prior bilateral ECT response, or extremely severe symptoms. Adverse cognitive effects have limited the popularity and use of ECT. Increased efficacy and side effects of ECT are correlated with higher intensities of the electrical current, and efficacy and side effects are also greater with bilateral ECT. The acute clinical benefits of ECT are usually time-limited, and most patients should receive longer-term continuation treatment with pharmacotherapy or with ECT. However, patients who failed to respond to adequate trials of antidepressant medication prior to ECT have a higher risk of relapsing with pharmacotherapy after successful ECT and therefore should preferentially receive continuation treatment with ECT.[88]

Repetitive transcranial magnetic stimulation (rTMS) is a novel noninvasive method for causing focal nonelectrical stimulation of the brain.[89] Unlike ECT, rTMS is not intended to cause seizures. With rTMS, a high intensity electrical current is passed through an electromagnetic coil on the scalp. Rapidly turning the current on and off generates repetitive pulses of a magnetic field that can be focused on particular regions of the brain, depending on the therapeutic intent. Low frequency stimulation inhibits neuronal excitability, whereas high frequency stimulation is excitatory. Typically, 5 rTMS sessions are administered weekly for 4 to 6 weeks for the treatment of depression. Adverse cognitive effects of rTMS are uncommon. Many short-term placebo-controlled studies (using sham rTMS) have used high-frequency rTMS focused on the left dorsolateral prefrontal cortex because this area is hypofunctional in depression.[90] Low-frequency rTMS focused on the right prefrontal cortex also is effective,[91]although this approach is less well studied than high-frequency left dorsolateral prefrontal cortex stimulation. Controlled studies of rTMS have found it effective in major depression,[92] including TRD.[93] Based on the results of a large multicenter study,[94] the use of rTMS has been approved by the FDA for the treatment of depressed patients who have not responded to a single antidepressant drug trial. The effectiveness of rTMS for more refractory forms of depression may be relatively less compared to ECT.[93]

The FDA approved vagus nerve stimulation (VNS) for refractory epilepsy in 1997 and for chronic TRD in 2005. The vagus nerve (cranial nerve X) is a parasympathetic nerve composed of afferent (carrying sensory information from the viscera) and efferent (regulating parasympathetic autonomic function) fibers. VNS involves the surgical implantation of a pacemaker-like programmable pulse generator, which is connected to and intermittently stimulates the left cervical vagus nerve. Studies in epilepsy patients found that VNS had positive effects on mood symptoms, and brain imaging and neurochemical studies have shown that VNS activates various limbic regions and affects various neurotransmitters. This work led to interest in studying VNS in depression. An open-label pilot study using VNS in a group of 60 chronic and highly treatment-resistant patients with unipolar or bipolar depression reported a response rate of approximately 40%.[95] VNS was very safe and generally well tolerated, similar to its safety and side effect profile in epilepsy. During long-term follow-up of 59 patients from this study, 44% were responders (27% remitters) at 1 year and 42% were responders (22% remitters) at 2 years.[96]

A multicenter randomized double-blind controlled acute treatment study comparing active VNS (device turned on) to sham VNS (device turned off) in 235 patients with chronic TRD did not find a statistically significant difference in response rates after 12 weeks of treatment (15% response with active VNS vs 10% with sham VNS).[97] At the end of this acute study, all patients received active VNS (device turned on) and were followed in a long-term treatment study.[98] A similar cohort of patients (with chronic depression or TRD) who did not receive VNS were recruited and followed long-term as a naturalistic control group.[99] After 1 year of follow-up, the VNS patients were significantly more likely to be improved (27% response; 16% remission) compared to the treatment-as-usual group (13% response; 7% remission). This study demonstrated that the effectiveness of VNS is well tolerated, increases with time, and is usually maintained, which is contrary to usual experience with pharmacotherapy in chronic TRD.[7] The use of VNS is safe and compatible with any psychotropic drug and with ECT, but cannot be used together with rTMS because of the magnetic effects of rTMS.

Neuroanatomic and brain imaging studies have identified a cortical-limbic-thalamic-striatal neural circuit that is important for understanding depression and obsessive-compulsive disorder (OCD).[100,101] Within this circuit, certain brain regions are relatively overactive whereas other regions are underactive. During the 1940s and 1950s, patients with severe intractable psychiatric disorders were sometimes treated by frontal lobotomy, so-called because these surgical procedures resulted in destruction of the white matter tracts of the frontal lobes of the brain. Although some patients improved, many others suffered irreversible personality deterioration as well as surgical complications. With the advent of psychotropic drug treatments, the use of this controversial treatment declined. Because available therapies are not always effective for some patients, the development of modern stereotactic neurosurgical methods[102] has led to a renewed interest in neurosurgical interventions. These involve the selective ablation or lesioning of particular brain regions that can be effective for TRD[103,104] and treatment-resistant OCD. Neurosurgical ablative therapy procedures for TRD include (1) anterior cingulotomy, (2) anterior capsulotomy, (3) subcaudate tractotomy, and (4) limbic leucotomy. Stereotactic neurosurgical methods have also been used to implant electrodes in the brain. Electrical stimulation by these electrodes with pacemaker-like devices can be used to modulate brain function, by stimulating or inhibiting the activity of specific brain regions, without causing permanent or destructive lesions that cannot be reversed.

The most widely used neurosurgical form of therapeutic brain stimulation is deep brain stimulation (DBS).[105] This involves the placement of stimulation electrodes into deep subcortical regions of the brain. The particular electrode placement depends on the condition being treated. Currently, DBS (with electrode placement in various basal ganglia) is an FDA-approved treatment for essential tremor,[106] Parkinson's disease,[107] and treatment-resistant OCD.[108-110] At least 5 different brain regions have been identified as potential targets for DBS in TRD.[111] Recent investigational studies of DBS for TRD have focused on 2 different regions: subgenual anterior cingulate (Brodmann area 25; Cg25), and ventral capsule/ventral striatum (VC/VS).

In depression, Cg25 is relatively overactive.[112] Twenty patients with TRD were enrolled in a pilot study using Cg25 DBS.[113] On average, the patients had been in a current episode of depression for 6 years and had failed at least 4 different antidepressant treatments. Seventeen patients had received ECT previously. One month after surgery, 35% of patients met criteria for response and 10% met criteria for remission. Six months after surgery, 60% of patients were responders and 35% met criteria for remission. These benefits were largely maintained at 12 months. The number of serious adverse effects was small with no patient experiencing permanent deficits. Three subjects had the device removed because of infection, but 1 of these subjects later had the device re-implanted. One perioperative seizure occurred. Transient adverse mood changes were noted in several patients. There were no adverse cognitive effects.

Another research group has focused on VC/VS DBS in patients with TRD. This region is close to where DBS for treatment-resistant OCD has been targeted. Studies of DBS for treatment-resistant OCD found that comorbid depression often improved. The VC/VS region is relatively underactive in depression.[101] In an initial report of a pilot study using VC/VS DBS for TRD, 5 patients were implanted.[114] By 3 months, 3 patients were responders and 2 patients were partial responders. In a subsequent report of 15 patients from this study followed from 6 months up to 4 years, the 6-month response rate was 47% and the remission rate was 27%.[115] At the last follow-up visit (mean of 24 months), the response rate was 53% and the remission rate was 33%. The patients in this study had been in a current episode of depression for at least 2 years and had failed about 12 different antidepressant treatments. All patients had received ECT and psychotherapy previously. The surgical procedure and stimulation with DBS were relatively well tolerated in these patients. Transient adverse mood changes were reported, but there were no adverse cognitive effects, seizures, infections, or other serious adverse events.

Discussion

For patients not responding adequately to an initial antidepressant medication, the 2 main approaches are switching or augmentation. The advantages of switching antidepressants include (1) typically greater empirical support for the efficacy of alternative antidepressants compared to most augmentation strategies, (2) less risk for adverse drug-drug interactions, (3) better compliance associated with monotherapy, and (4) generally lower cost associated with monotherapy. Disadvantages of switching include (1) potential clinical worsening associated with discontinuing a partially effective antidepressant, (2) a delay in the time to a therapeutic response to the new medication, and (3) the loss of potentially beneficial additive or synergistic drug-drug interactions. Advantages of augmentation include (1) easy implementation, (2) avoiding clinical worsening associated with discontinuing a partially effective antidepressant, (3) potentially rapid treatment response, and (4) gaining possibly beneficial additive or synergistic effects by combining drugs with different mechanisms of action. Disadvantages of augmentation include (1) greater risk for adverse effects or toxicity, (2) increased cost, and (3) poor compliance associated with polypharmacy.

Given the availability of a wide variety of potentially effective therapies, how does one choose among these treatments? Patient preference is important to consider. Patients who strongly favor medication or psychotherapy should be offered treatment as such. The choice of medication will depend on such factors as patient preference, treatment history, family treatment history, clinical symptoms, and expected side effect profile. For TRD, whether to switch, combine, or augment medications should depend on the availability of comparative data on the relative efficacy, tolerability, and acceptability of the treatment options. In the STAR*D study,[120] an equipoise stratified randomized design was used, such that patients could accept or decline particular treatments (similar to clinical practice) as long as sufficient options were left that allowed a randomization between at least 2 different options. Most patients only agreed to have their medication either switched or augmented; relatively few patients agreed to do both. As a result, definitively comparing strategies involving augmentation with those involving a switch could not be done.

Among depressed patients, a significant minority do not have a satisfactory response to sequential trials of various drug-drug and drug-psychotherapy combinations. ECT often is considered the treatment of choice for these patients. However, ECT may not be efficacious, well tolerated, or acceptable, or it may be contraindicated. Novel alternative approaches for TRD include various types of alternative neurostimulation therapies and neurosurgical therapy procedures. Potential noninvasive neurostimulation therapies for TRD include rTMS, but it may have limited efficacy for patients with extensive treatment failure histories. Among the invasive neurostimulation therapies, VNS is often positioned as a treatment for ECT-intolerant or ECT-resistant depression. Other investigational invasive neurostimulation therapies include DBS. Neurosurgical ablative therapy procedures would then be considered as a treatment of last resort.