Jan Fawcett

Antidepressant Drug effects and Depression Severity: A Patient-Level Meta-Analysis

CONTEXT Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. OBJECTIVE To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. DATA SOURCES PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. STUDY SELECTION Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. DATA EXTRACTION Individual patient-level data were obtained from study authors. RESULTS Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. CONCLUSIONS The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression

Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.

Gender Differences in the Clinical Features of Unipolar Major Depressive Disorder

Gender differences in the presence or absence and the severity of forty-seven clinician rated features of depression were examined, controlling for the sex of the rater. Subjects consisted of 498 moderately to severely depressed patients coming for treatment and diagnosed as suffering from nonpsychotic, unipolar major depressive disorder. Significant differences were found only for increased appetite and weight. No differences were observed in endogenous symptoms, global severity of depression, or impairment in functioning. The results indicate that, although the rate of major depressive disorder is greater in women, its symptomatology is relatively homogeneous with regard to gender.

ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth

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.

Fluoxetine efficacy in menopausal women with and without estrogen replacement

UNLABELLED A gradual decline in estrogen levels after the age of 40 may contribute to a higher rate of depression in women over 45 years of age. Estrogen replacement therapy (ERT) has been shown to produce cognitive and mood-enhancing effects in women and may facilitate antidepressant activity. METHODS We examined the efficacy rates in women on ERT > or = 45 years (n = 40) compared to women > or = 45 years not on ERT (n = 132) and to women < 45 years (n = 396) and to men (n = 262) with major depression during fluoxetine 20 mg daily up to 8 weeks. Remitters with a HAM-D17 score < or = 7 from week 9 to 12 were then treated up to 1-year in a placebo-controlled, relapse-prevention trial. RESULTS Efficacy rates were similar in women > or = 45 years on ERT when compared to women > or = 45 years taking fluoxetine alone, and when compared to women < 45 years and men taking fluoxetine. A Kaplan-Meier survival analysis in fluoxetine responders treated up to 26 weeks showed a somewhat greater relapse rate in women > or = 45 years taking ERT compared to other treatment groups (P < 0.06). LIMITATIONS This study was retrospective nature and ERT was given in an uncontrolled fashion: 63% of women received estrogen alone while 37% also took intermittent progesterone. Other variables include the absence of hormonal documentation of menopausal status, no direct assessment of ERT compliance and the use of fixed-dose fluoxetine 20 mg daily. CONCLUSION In contrast to prior reports suggesting that ERT may facilitate antidepressant activity, we observed similar efficacy in depressed women > or = 45 years taking fluoxetine plus ERT compared to those taking fluoxetine alone.

Urinary catecholamine metabolites during behavioral changes in a patient with manic-depressive cycles.

3-Methoxy-4-hydroxyphenylglycol and normetanephrine were analyzed in daily urine specimens of a patient with manic-depressive cycles who was studied longitudinally. The quantities of these catecholamine metabolites excreted into urine were decreased during periods of depression as compared with periods of mania. Urinary excretion of 3-methoxy-4-hydroxyphenylglycol varied cyclically with a period length of approximately 20 days. Changes in this metabolite, and perhaps in normetanephrine, preceded the affective and behavioral shifts.

Self-Reported Depressive Symptom Measures: Sensitivity to Detecting Change in a Randomized, Controlled Trial of Chronically Depressed, Nonpsychotic Outpatients

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-I) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-I, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 1–4, 6, 8, 10, and 12. Response was defined a priori as a ⩾50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-I score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-I), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-I), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-I), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30=32%, QIDS-SR16=28%, PGI-I=22%, HDRS17=30%), for CBASP (IDS-SR30=32%, QIDS-SR16=30%, PGI-I=21%, HDRS17=32%), and for the combination (IDS-SR30=52%, QIDS-SR16=50%, PGI-I=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-I, as opposed to specific item-based ratings, provide less valid findings.

Treating Impulsivity and Anxiety in the Suicidal Patient

Abstract: It has been found that while over 90% of people who commit suicide have a psychiatric illness at the time, over 50% are under active psychiatric or mental health care. How can suicide risk be detected and preventive treatment provided? Both communication of suicidal ideation or intent and prior suicide attempts have been shown to be risk factors, which should be assessed in patients with psychiatric illness. Research shows that suicidal ideation is often not communicated to professionals or is denied by patients just prior to suicide and, when present, is often useful not as an immediate risk factor, but as a chronic risk factor. Suicide attempts predict a 10‐30% occurrence of suicide over 10 years, but often do not indicate immediate risk. Recent research has shown that impulsiveness and severe anxiety, panic attacks, and agitation comorbid with depression are often immediate suicide risk factors that are potentially modifiable if recognized and treated urgently with effective medications and watchful support.

CNS STIMULANT POTENTIATION OF MONOAMINE OXIDASE INHIBITORS IN TREATMENT-REFRACTORY DEPRESSION

We report on our clinical experience with a combination of a CNS stimulant (either pemoline or dextroamphetamine) and a monoamine oxidase inhibitor (MAOI) for treating 32 depressed patients (mainly outpatients) refractory to standard antidepressant pharmacotherapy. This combination, though not approved by the FDA, appears to be safe and effective. Twenty-five (78%) of these patients experienced at least 6 months of symptom remission with a stimulant + MAOI combination. Many patients required adjunctive antidepressant treatment, including tricyclics and lithium. Side effects were not excessive, though 6 patients (3 unipolar and 3 bipolar) cycled to mania (N = 1) or hypomania (N = 5). None developed hypertensive crises. With properly motivated and complaint patients and careful clinical monitoring by the prescribing psychiatrist, stimulant potentiation of MAOIs may be a viable option for treatment-resistant depressed patients.

Suicide: A Four-pathway Clinical-Biochemical Model

Abstract This chapter, based on a review of recent research as well as data presented in this report, proposes four hypothetical pathways leading to suicide in clinical depression: (1) an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin‐releasing factor (CRF or CRH) levels, (2) trait baseline and reactivity hopelessness, (3) severe anhedonia, and (4) trait impulsiveness associated with low brain serotonin turnover and low total cholesterol as a possible peripheral correlate.