CONTEXT Extracts of Hypericum perforatum (St John's
wort) are widely used for the treatment of depression of varying severity.
Their efficacy in major depressive disorder, however, has not been ...conclusively
demonstrated. OBJECTIVE To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING Double-blind, randomized, placebo-controlled trial conducted in 12 academic
and community psychiatric research clinics in the United States. PARTICIPANTS Adult outpatients (n = 340) recruited between December 1998 and June
2000 with major depression and a baseline total score on the Hamilton Depression
Scale (HAM-D) of at least 20. INTERVENTIONS Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based
on clinical response, the daily dose of H perforatum
could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg.
Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES Change in the HAM-D total score from baseline to 8 weeks; rates of full
response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression
parameter estimate for mean (SE) change in HAM-D total score from baseline
to week 8 (with a greater decline indicating more improvement) was –9.20
(0.67) (95% confidence interval CI, –10.51 to –7.89) for placebo
vs –8.68 (0.68) (95% CI, –10.01 to –7.35) for H perforatum (P = .59) and –10.53 (0.72)
(95% CI, –11.94 to –9.12) for sertraline (P = .18). Full response occurred in 31.9% of the placebo-treated patients
vs 23.9% of the H perforatum–treated patients
(P = .21) and 24.8% of sertraline-treated patients
(P = .26). Sertraline was better than placebo on
the CGI improvement scale (P = .02), which was a
secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. CONCLUSION This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low
assay sensitivity of the trial, but the complete absence of trends suggestive
of efficacy for H perforatum is noteworthy.
The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic ...properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.
Citalopram, the most selective serotonin reuptake inhibitor (SSRI), is a bicyclic phthalane derivative with a chemical structure that is unrelated to that of other SSRIs and available ...antidepressants. The drug is approved for use in 69 countries. This 6-week, fixed-dose, placebo-controlled, parallel-arm, multicenter trial was performed to confirm its efficacy and safety in treatment of outpatients with major depression in the United States.
Six hundred and fifty adult outpatients with moderate-to-severe major depression (DSM-III-R) were randomly assigned to receive citalopram at doses of 10 mg (N = 131), 20 mg (N = 130), 40 mg (N = 131), or 60 mg (N = 129) or placebo (N = 129) once daily. Outcome assessments were the 21-item Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale.
Between-group comparisons of the change from baseline to endpoint revealed significantly greater improvement in the citalopram patients relative to the placebo patients on all 3 efficacy measures. Patients randomly assigned to 40 mg/day and 60 mg/day of citalopram showed significantly greater improvement than placebo on all efficacy measures, as well as on the HAM-D symptom clusters measuring depressed mood, melancholia, cognitive disturbance, and psychomotor retardation. Patients who received 10 mg/day and 20 mg/day of citalopram also showed consistent improvement relative to placebo on all efficacy ratings, with statistical significance demonstrated in the MADRS response rate, the HAM-D depressed mood item, and the HAM-D melancholia subscale. Citalopram was well tolerated, with only 15% of patients discontinuing for adverse events. The side effects most commonly associated with citalopram treatment were nausea, dry mouth, somnolence, insomnia, and increased sweating.
Citalopram was significantly more effective than placebo in the treatment of moderate-to-severe major depression, especially symptoms of depressed mood and melancholia, with particularly robust effects shown at doses of 40 and 60 mg/day. Citalopram was well tolerated in spite of forced upward titration to fixed-dose levels, with a low incidence of anxiety, agitation, and nervousness.
A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective ...disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S. BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (> or = 30% reduction) and the CGI improvement (score < or = 2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.
The syndromes of anxiety and depression may reflect separate disorders with overlapping symptoms. They also may be comorbid or reflect illnesses with similar underlying pathophysiology based upon a ...spectrum of central nervous system dysfunction. Antidepressants effectively treat both anxiety and comorbid anxiety-depression. Tertiary tricyclic antidepressant agents (TCAs) with dual serotonergic-noradrenergic effects, such as imipramine and amitriptyline, appear consistently effective across the anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are particularly effective in panic disorder and obsessive-compulsive disorder. SSRIs are similar in efficacy to TCAs but are more tolerable and cause fewer serious adverse events. However, they are relatively slow to act, and efficacy data are limited in states such as generalized anxiety disorder. Newer antidepressants, such as mirtazapine, nefazodone, and venlafaxine XR, may provide some benefits across the broad spectrum of anxiety disorders with the safety and tolerability that are the hallmarks of third generation antidepressants.
We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study.
...Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale.
Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively.
Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.
Clinical data were evaluated from an open-label, single-center, pilot study in patients with chronic refractory depression. The primary efficacy criterion was the change from baseline using the ...Montgomery–Asberg Depression Rating Scale. The secondary efficacy criteria were the 17-item Hamilton Depression Rating Scale and the Clinical Global Impression-Improvement scale. Response to treatment (40–240 mg once per day by subcutaneous injection for 10–20 doses) was defined as more than 50% improvement in the Montgomery–Asberg Depression Rating Scale from baseline or Clinical Global Impression-Improvement ≤2 and lasting for at least two sequential weeks. Patients with a sustained response at the end point in the acute main treatment phase were enrolled for up to 2 years in a maintenance phase of the study to determine duration of response and to initiate retreatments upon relapse. Of the 25 patients with chronic refractory depression, 11 patients showed a response for Montgomery–Asberg Depression Rating Scale and one responded according to the secondary criterion Hamilton Depression Rating Scale. In seven of the 11 responders to Montgomery–Asberg Depression Rating Scale the effects were sustained for the remainder of the acute phase. Two additional sustained responders identified according to secondary criteria (Hamilton Depression Rating Scale or Clinical Global Impression-Improvement) were also enrolled in the maintenance phase. All nine sustained responders were retreated, as needed, in the maintenance phase of the study, ranging from 71 to 660 days. Mean duration of response following initial treatment and between retreatments was around 2 months. Pharmacokinetic data indicated dose-proportional systemic exposure to the drug.
We assessed the tolerability and utility of switching fluoxetine nonresponders to citalopram the day that fluoxetine therapy was stopped.
Fifty-eight outpatients with DSM-IV major depressive episode ...and prospectively confirmed nonresponse to fluoxetine (mean final dose = 31 mg/day) were switched directly to citalopram (20 mg/day). Of the 58 patients, 44 (76%) had never been successfully treated with antidepressant medication. During a 12-week open-label treatment period, citalopram could be titrated up to a maximum dose of 60 mg/day. Response was evaluated using the Clinical Global Impressions (CGI) scale, the 24-item Hamilton Rating Scale for Depression, and several other measures.
Eighty-one percent (N = 47) completed the trial, and citalopram (mean dose = 38.8 mg/day) was well tolerated. The intent-to-treat CGI response rate was 46% (26/57) at week 6 and 63% (36/57) at study endpoint; the completer response rate was 76% among the 47 patients who completed the 12-week trial. Improvement from baseline on all dependent measures was statistically significant after the first week of citalopram treatment.
Fluoxetine nonresponders can be quickly switched to citalopram, with good tolerability and reasonable chance of therapeutic benefit. Further work is necessary to assess the merits of this treatment strategy relative to other options.
The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors ...(MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.
Nemifitide is a novel peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period.
The Flinders Sensitive Line (FSL) rat, a ...genetic animal model of depression with innate exaggerated immobility in the forced swim test, was used to obtain more detailed information about the antidepressant-like effects of nemifitide.
The FSL rats were treated chronically with various doses of nemifitide or reference antidepressants desipramine and fluoxetine for 5 or 14 days and the forced swim test was conducted 22-24 h after the last treatment.
Nemifitide significantly increased swimming in the FSL rats at both low (0.025-0.3 mg/kg) and high (3.0-15.0 mg/kg) doses but not at intermediate (0.4-2.4 mg/kg) doses. Nemifitide (0.3 mg/kg) and desipramine (5.0 mg/ kg) significantly increased swimming in the FSL rats after just 5 days of treatment, but fluoxetine (5.0 mg/kg) did not. Nemifitide (0.3 mg/kg) and fluoxetine (5.0 mg/kg) had long-lasting effects, but desipramine (5.0 mg/kg) did not.
These findings support the value of developing nemifitide and its analogs as potential antidepressants.
PDF
