Abstracts Psychopharmacology

Given space limitations and varying reprint permission policies, not all of the influential publications the editors considered reprinting in this issue could be included. This section contains abstracts from additional articles the editors deemed well worth reviewing.

Randomized Controlled Trial of the Effect on Quality of Life of Second- vs First-generation Antipsychotic Drugs in Schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1)

Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW

Archives of General Psychiatry October 2006; 63:1079–1087

Context: Second-generation (atypical) antipsychotics (SGAs) are more expensive than first-generation (typical) antipsychotics (FGAs) but are perceived to be more effective, with fewer adverse effects, and preferable to patients. Most evidence comes from short-term efficacy trials of symptoms. Objective: To test the hypothesis that in people with schizophrenia requiring a change in treatment, SGAs other than clozapine are associated with improved quality of life across 1 year compared with FGAs. Design: A noncommercially funded, pragmatic, multisite, randomized controlled trial of antipsychotic drug classes, with blind assessments at 12, 26, and 56 weeks using intention-to-treat analysis. Setting: Fourteen community psychiatric services in the English National Health Service. Participants: Two hundred twenty-seven people aged 18 to 65 years with DSM-IV schizophrenia and related disorders assessed for medication review because of inadequate response or adverse effects. Interventions: Randomized prescription of either FGAs or SGAs (other than clozapine), with the choice of individual drug made by the managing psychiatrist. Main Outcome Measures: Quality of Life Scale scores, symptoms, adverse effects, participant satisfaction, and costs of care. Results: The primary hypothesis of significant improvement in Quality of Life Scale scores during the year after commencement of SGAs vs FGAs was excluded. Participants in the FGA arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores. Participants reported no clear preference for either drug group; costs were similar. Conclusions: In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs. Neither inadequate power nor patterns of drug discontinuation accounted for the result.

A Comparison of Lithium and T(3) Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report

Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ.

American Journal of Psychiatry September 2006; 163:1519–1530

Objective: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T(3)) augmentation as a third-step treatment for patients with major depressive disorder. Method: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T(3) (up to 50 μg/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score ⩽7 on the 17-item Hamilton Depression Rating Scale. Results: After a mean of 9.6 weeks (SD=5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T(3) augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p=0.027). Conclusions: Remission rates with lithium and T(3) augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T(3) augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.

Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials For Depression: A STAR*D Report

McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, Thase ME, Davis L, Biggs MM, Shores-Wilson K, Luther JF, Niederehe G, Warden D, Rush AJ

American Journal of Psychiatry September 2006; 163:1531–1541

Objective: The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. Method: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score ⩽7 at exit on the 17-item Hamilton Depression Rating Scale (HAM-D). The HAM-D was administered by telephone by raters to whom treatment was masked. Results: Remission rates were not significantly different between the two treatment groups (6.9% for the tranylcypromine group and 13.7% for the venlafaxine plus mirtazapine group). The mean daily dose at exit for tranylcypromine was 36.9 mg (SD=18.5); for venlafaxine, 210.3 mg (SD=95.2); and for mirtazapine, 35.7 mg (SD=17.6). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance. Conclusions: Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments.

Clinical Differences Among Depressed Patients With and Without a History of Suicide Attempts: Findings from the STAR*D Trial

Claassen CA, Trivedi MH, Rush AJ, Husain MM, Zisook S, Young E, Leuchter A, Wisniewski SR, Balasubramani GK, Alpert J

Journal of Affective Disorders July 2006; 4

Background: This study sought to determine whether a history of suicide attempts among outpatients diagnosed with nonpsychotic major depressive disorder (MDD) is correlated with any difference in clinical presentation that should influence patient care. Methods: Baseline data from the Sequenced Treatment Alternatives to Relieve Depression (STAR()D) trial on outpatients with MDD treated in primary and specialty care settings were used to model significant demographic and clinical correlates of suicide attempter status. Results: Altogether, 16.5% of participants (n=667) reported prior suicide attempts. Controlling for age, gender, and depressive symptom severity, previous attempters had more current general medical conditions (μ=3.2 vs. 2.9, p<.0001), more current alcohol/substance abuse (p<.0001), and more work hours missed in the past week (26.2% vs. 18.2%, p<.0001) than non-attempters. On average, for the previously suicidal, the onset of MDD occurred 8.9 years earlier in life (p<.0001) and had included 1.2 additional depressive episodes (p<0.001) compared to those without prior suicidal behavior. Previous attempters also reported more current suicidal ideation (61.3% of previous attempters, adjusted OR 1.6, vs. 45.5% of nonattempters, p<.0001). Limitations: Presence or absence of a history of suicide attempts was determined only through self report. Conclusions: Those with a history of suicidal behavior suffer a greater burden of depressive illness. Earlier intervention and ongoing, aggressive care, including maintenance-phase pharmacotherapy, may be critical to mitigating the long-term consequences associated with this increased disease burden.

A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report

Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther JF, Niederehe G, Ritz L, Trivedi MH

American Journal of Psychiatry July 2006; 163:1161–1172

Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of ⩽7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)), obtained at treatment visits, provided secondary outcomes of remission (score ⩽5 at exit) and response (⩾50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR(16) response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.

A Systematic Review of Modafinil: Potential Clinical Uses and Mechanisms of Action

Ballon JS, Feifel D

Journal of Clinical Psychiatry April 2006; 67(4):554–566

Background: Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil. Data Sources: The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil. Data Synthesis: There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil’s use abound in the literature. Conclusions: Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth

Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, Wagner KD

Neuropsychopharmacology March 2006; 31(3):473–492

This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.

The Nature of the Discontinuation Syndrome Associated with Antidepressant Drugs

Shelton RC

Journal of Clinical Psychiatry 2006; 67 Suppl 4:3–7

A common phenomenon accompanying treatment with nearly every major class of antidepressant is the emergence of the discontinuation syndrome in some patients. It is seen most frequently after the abrupt cessation of agents with shorter half-lives. The term withdrawal has been used in the past; however, the distinctions between discontinuation symptoms and drug withdrawal are clear. Thus, the use of proper terminology when discussing this phenomenon with patients will help to alleviate concerns and stop the spread of common misperceptions. In addition, awareness of the unique nature of discontinuation effects and a grasp of the typical time frame of their emergence can assist in distinguishing between discontinuation syndrome and relapse. As a result, it is vital that both patients and their relatives, especially caregivers, be provided with adequate education and a realistic and objective appraisal of expected outcomes upon initiation of antidepressant treatment.

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators

New England Journal of Medicine September 22, 2005; 353(12):1209–1223

Background: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. Methods: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Results: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. Conclusions: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

Treatment of Attention-Deficit/Hyperactivity Disorder: Overview of the Evidence

Ronald T. Brown, PhD, Robert W. Amler, MD, Wendy S. Freeman, PhD, James M. Perrin, MD, Martin T. Stein, MD, Heidi M. Feldman, MD, PhD, Karen Pierce, MD, Mark L. Wolraich, MD and the Committee on Quality Improvement, Subcommittee on Attention-Deficit/Hyperactivity Disorder

Pediatrics Vol. 115 No. 6 June 2005, pp. e749–e757

The American Academy of Pediatrics’ Committee on Quality Improvement, Subcommittee on Attention-Deficit/Hyperactivity Disorder, reviewed and analyzed the current literature for the purpose of developing an evidence-based clinical practice guideline for the treatment of the school-aged child with attention-deficit/hyperactivity disorder (ADHD). This review included several key reports, including an evidence review from the McMaster Evidence-Based Practice Center (supported by the Agency for Healthcare Research and Quality), a report from the Canadian Coordinating Office for Health Technology Assessment, the Multimodal Treatment for ADHD comparative clinical trial (supported by the National Institute of Mental Health), and supplemental reviews conducted by the subcommittee. These reviews provided substantial information about different treatments for ADHD and their efficacy in improving certain characteristics or outcomes for children with ADHD as well as adverse effects and benefits of multiple modes of treatment compared with single modes (eg, medication or behavior therapies alone). The reviews also compared the effects of different medications. Other evidence documents the long-term nature of ADHD in children and its classification as a chronic condition, meriting the application of general concepts of chronic-condition management, including an individual treatment plan with a focus on ongoing parent and child education, management, and monitoring. The evidence strongly supports the use of stimulant medications for treating the core symptoms of children with ADHD and, to a lesser degree, for improving functioning. Behavior therapy alone has only limited effect on symptoms or functioning of children with ADHD, although combining behavior therapy with medication seems to improve functioning and may decrease the amount of (stimulant) medication needed. Comparison among stimulants (mainly methylphenidate and amphetamines) did not indicate that one class outperformed the other.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Suicide in Adults: Meta-analysis of Drug Company Data from Placebo Controlled, Randomised Controlled Trials Submitted to the MHRA’s Safety Review

Gunnell D, Saperia J, Ashby D

British Medical Journal February 19, 2005; 330:385–388

Objective: To investigate whether selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with an increased risk of suicide related outcomes in adults. DESIGN: Meta-analysis of randomised controlled trials of SSRIs compared with placebo in adults submitted by pharmaceutical companies to the safety review of the Medicines and Healthcare products Regulatory Agency (MHRA). Participants: Over 40,000 individuals participating in 477 randomised controlled trials. Main Outcome Measures: Suicide, non-fatal self harm, and suicidal thoughts. Results: An estimated 16 suicides, 172 episodes of non-fatal self harm, and 177 episodes of suicidal thoughts were reported. We found no evidence that SSRIs increased the risk of suicide, but important protective or hazardous effects cannot be excluded (odds ratio 0.85, 95% credible interval 0.20 to 3.40). We found weak evidence of an increased risk of self harm (1.57, 0.99 to 2.55). Risk estimates for suicidal thoughts were compatible with a modest protective or adverse effect (0.77, 0.37 to 1.55). The relative frequency of reported self harm and suicidal thoughts in the trials compared with suicide indicates non-fatal end points were under-recorded. Conclusion: Increased risks of suicide and self harm caused by SSRIs cannot be ruled out, but larger trials with longer follow up are required to assess the balance of risks and benefits fully. Any such risks should be balanced against the effectiveness of SSRIs in treating depression. When prescribing SSRIs, clinicians should warn patients of the possible risk of suicidal behaviour and monitor patients closely in the early stages of treatment.

Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents With Depression: Treatment for Adolescents With Depression Study (TADS) Randomized Controlled Trial

March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team

The Journal of The American Medical Association 2004 August 18; 292(7):807–820

Context: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. Design, Setting, and Participants: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures: Children’s Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children’s Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%– 80%); fluoxetine alone, 60.6% (95% CI, 51%–70%); CBT alone, 43.2% (95% CI, 34%–52%); and placebo, 34.8% (95% CI, 26%– 44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.

Lamotrigine Treatment of Bipolar Disorder: Data From the First 500 Patients in STEP-BD

Lauren B Marangell, James M Martinez, Terence A Ketter, Charles L Bowden, Joseph F Goldberg, Joseph R Calabrese, Sachiko Miyahara, David J Miklowitz, Gary S Sachs and Michael E Thase for the STEP-BD investigators

Bipolar Disorder April 2004; 6(2):139–143

Objective: To describe the frequency and correlates of lamotrigine therapy among the first 500 patients enrolled into the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. Method: Systematic recording of psychiatric history and medication data at intake into the STEP-BD project. Results: Of the participants with bipolar disorder type I or II (n = 483), 77 (15.4%) were currently taking lamotrigine (mean dose: 258.12 mg/day) and 52 (10.4%) reported prior lamotrigine use. The groups were comparable with regard to duration of illness and mood state at study entry. Compared with participants who had never taken lamotrigine, those currently treated with lamotrigine were significantly more likely to have a prior history of rapid cycling (62.5% vs. 43.1%; p < 0.01) and an antidepressant-induced switch to (hypo)mania (49.3% vs. 33.3%; p < 0.01). In contrast, only 16.9% of lamotrigine-treated participants were taking an anti-depressant at study intake, as compared with 29.1% of participants with no history of lamotrigine therapy (p < 0.03). Conclusions: While noting the limitations of a cross-sectional assessment, these data suggest that lamotrigine therapy was commonly used in these academic centers for patients with bipolar disorder several years before it was recommended in the American Psychiatric Association practice guidelines, particularly in patients with a history of rapid cycling or antidepressant-induced mania.

Comparing the Methods to Use to Compare Antidepressants

Thase ME

Psychopharmacology Bulletin Spring 2002; 36:Suppl 1

A wide array of antidepressants are now available to treat depression. However, the conventional wisdom that these medications are equally effective may not be true. It is argued that most randomized controlled trials (RCTs) do not have the power to discriminate between an effective and an even more effective medication. Until RCTs that enroll 300 or more patients per arm are conducted, or more sensitive research designs are developed, it will be difficult to determine if a “not statistically different” finding reflects true therapeutic equivalence or if it is a false-negative result (or type II error). Statistical methods that evaluate data from a number of studies are used increasingly to compare treatment strategies. The relative merits and limitations of quantitative meta-analysis and pooled analysis of original data are discussed. The former method is preferred when a large number of relevant RCTs can be analyzed. Beyond the number of studies, publication bias (“file drawer” effect) and study selection criteria may influence outcomes of meta-analysis. Pooled analysis, which combines all original patient data, is preferred when there are only a handful of related RCTs. However, the integrity of a pooled analysis can be ruined by selective inclusion of studies (“cherry picking”). The validity of combining the data from different studies also must be demonstrated. Results of studies using these complementary methods suggest that there may be clinically meaningful differences in efficacy between several classes of antidepressants.