Эффективность использования высоких доз антидепрессантов

Higher doses than those currently used might be modestly more effective, but come with higher risks of adverse effects.

Before writing medications off as ineffective or only partially effective, clinicians strive to optimize dosing. To better identify optimal doses for six selective serotonin reuptake inhibitors (SSRIs), investigators applied meta-analytic techniques to 40 studies involving 10,039 patients with major depression in placebo-controlled randomized trials who were treated with fluoxetine, (N=2386), fluvoxamine (N=910), paroxetine (N=3424), sertraline (N=865), citalopram (N=1349), or escitalopram (N=1105).

Focusing on efficacy and tolerability, investigators calculated number needed to treat (NNT) and number needed to harm (NNH). They used published dose ranges to convert SSRI doses to imipramine equivalents, with 100 mg of imipramine equivalent to:

Sertraline, 120 mg

Fluvoxamine, 100 mg

Paroxetine, 20 mg

Fluoxetine, 20 mg

Citalopram, 33.3 mg

Escitalopram, 16.7 mg

Statistical modelling adjusted for lag times of medication-effect onsets and for doses used in the trials (100–400 mg of imipramine equivalents). In dose-by-time interaction analyses, higher doses yielded greater therapeutic responses. Greatest efficacy was seen for 200–250-mg imipramine equivalents, compared with higher and lower ranges (NNTs: compared with placebo, 3; in lower-dose comparisons, 14–16). Compared with low doses, higher dose was associated with greater likelihood of dropout due to adverse effects (NNHs, 45–48), but all-cause dropouts were fewer at higher doses, presumably due to efficacy. Fluvoxamine, approved for depression in other countries but not by the FDA, was excluded in some analyses, which yielded similar overall results.

Comment

These findings generally support the use of higher dose ranges for several SSRIs for major depression that did not respond or only partially responded to SSRIs. Most clinicians treating obsessive-compulsive disorder and bulimia nervosa are already comfortably using these higher doses. However, distinctions among SSRIs are warranted; for example, the FDA has issued warnings about QTc interval prolongation with higher doses of citalopram.

 Optimal Doses for SSRIs in Treating Depression: Meta-Analytic Results

Упражнения, депрессии, цитокины

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P < 0.0001). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (P = 0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.

 Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder

Вортиоксетин

Denmark's Lundbeck today announced positive trial results with the experimental antidepressant Brintellix (vortioxetine) in adults with major depression (MDD) who changed antidepressant treatment after an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI).

The double-blind randomized REVIVE study compared the efficacy and tolerability of flexible dose treatment with Brintellix (10-20mg/day) versus agomelatine (25-50 mg/day) in nearly 500 patients with resistant MDD.

 Experimental Antidepressant Vortioxetine Shows Positive Results

Целесообразность потенцирования атипичными антипсихотиками при депрессии

For the study, researchers reviewed 14 previous randomized clinical trials in which the combined use of an antidepressant and an antipsychotic medication were compared to the use of an antidepressant with a placebo.

The medications investigated in the studies were aripiprazole (Abilify), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel) and risperidone (Risperdal).

The results showed a small benefit with antipsychotic use on relieving the symptoms of depression. But when the researchers looked for a more meaningful outcome — whether the patients’ quality of life had improved — no benefit was found.

...

Antipsychotic medications were associated, however, with more negative side effects, including weight gain, akathisia (a feeling of restlessness), sleepiness and abnormal results from cholesterol and other metabolic-related laboratory tests.

In another study, British researchers found strong evidence that engaging in talk therapy was an effective add-on to antidepressants.

The findings showed that antidepressant-resistant patients who received cognitive behavioral therapy in addition to an antidepressant experienced both a significant reduction in their depression and a significant improvement in their quality of life.

Adding Antipsychotic Meds to Antidepressants Shows Risk, Little Benefit

Эффективность сочетания холекальциферола с флуоксетином

Objective: To compare the therapeutic effects of vitamin D3 plus fluoxetine and fluoxetine alone in patients with major depressive disorder.
Methods: In the present double-blind, randomized, placebo-controlled trial, 42 patients with a diagnosis of major depressive disorder based on DSM-IV criteria were randomly assigned into two groups to receive daily either 1500 IU vitamin D3 plus 20 mg fluoxetine or fluoxetine alone for 8 weeks. Depression severity was assessed at 2-week intervals using the 24-item Hamilton Depression Rating Scale (HDRS) as a primary outcome measure and the 21-item Beck Depression Inventory (BDI) as a secondary outcome measure. Serum 25(OH) vitamin D was measured at baseline and after intervention.
Results: Forty patients completed the trial. A two-way repeated-measures analysis of variance showed that depression severity based on HDRS and BDI decreased significantly after intervention, with a significant difference between the two groups. The vitamin D + fluoxetine combination was significantly better than fluoxetine alone from the fourth week of treatment.
Conclusions: In the present 8-week trial, the vitamin D + fluoxetine combination was superior to fluoxetine alone in controlling depressive symptoms.

 Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder

Полиморфизм CYP2D6 и приверженность лечению антидепрессантами

Early discontinuation of antidepressant drugs (ADPs) therapy is common, occurring in about 30% of patients by week 6.1, 2 Among the most relevant reasons for ADP discontinuation are adverse drug reactions and lack of improvement,3 which can be explained by interindividual variability in drug metabolism. Thus, discontinuation of amitriptyline or fluoxetine, two of the most commonly used ADPs worldwide, which are mainly metabolized by CYP2D6, could be related to CYP2D6 genetic polymorphism.

...

Despite the limitations of the present study (naturalistic observation, non-fixed dose, lack of evaluation of drug plasma concentrations and efficacy), a relationship between CYP2D6 polymorphism and early discontinuation of fluoxetine or amitriptyline monotherapy treatment was observed. There were differences across CYP2D6 groups in the rate of ADP discontinuation at week 4 (P < 0.01;Table 1). Overall, the rates of ADP discontinuation were 25, 36 and 46% at weeks 4, 8 and 12, respectively; no patient returned after dropout. All UMs discontinued treatment within the first 4 weeks, whereas no PM did so within 12 weeks.

 CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients

Экспериментальные антидепрессанты AZD6765 и GLYX-13

A small, randomized crossover study conducted by investigators at the National Institute of Mental Health Health (NIMH) showed that after a single infusion of AZD6765, almost 32% of the patients with treatment-resistant major depressive disorder (MDD) had a significant decrease in symptom scores 80 minutes later vs 15% of the patients after they had received matching placebo.

Although after receiving the experimental drug, the total decrease in scores lasted only for 30 minutes, some of the patients did experience residual antidepressant effects up to 2 days later.

 Experimental Drug May Help Depression 'in Minutes'

In clinical trials administered at 12 sites across the country, a single dose of GLYX-13 resulted in significant reductions in depression symptoms among subjects who had shown little improvement with previous drugs. (Subjects had failed treatment with one or more antidepressant agents.)

The positive effects of GLYX-13 were evident within 24 hours and lasted an average of seven days. Side effects of GLYX-13 were mild to moderate and were consistent with those observed in subjects receiving a placebo.

New Fast-Acting Antidepressant, GLYX-13, Shows Promise in Clinical Trials

Аспирин снижает риск депрессии у людей с повышенным уровнем гомоцистеина

High total plasma homocysteine (tHcy) is associated with increased risk of cardiovascular events and depression. Consumption of B-vitamins (B6, B9 and B12) reduces tHcy by about 15%, but has equivocal effects on these health outcomes, suggesting that this relationship is either not causal or is confounded by other factors. The results of recent randomized trials suggest that antiplatelet therapy may confound these associations. This cross-sectional study assessed 3687 men aged 69–87 years for history of clinically significant depression (Geriatric Depression Scale 15 items 7) or a recorded diagnosis of depression in the Western Australian Data Linkage System, and collected information on the use of aspirin, B-vitamins and antidepressant medication, along with age, education, living arrangements, smoking history and medical comorbidity as assessed by the Charlson index. Participants donated a blood sample for the measurement of tHcy, and concentrations15 μmol l−1 were considered high. Five hundred and thirteen (13.9%) men showed evidence of depression, and of those 31.4% had high tHcy, 41.5% were using aspirin, 6.8% were consuming B-vitamins. Multivariate logistic regression showed that high tHcy was associated with increased odds of depression (odds ratio (OR)=1.60, 95% confidence interval (CI)=1.20–2.14), as was the use of B-vitamins (OR=1.95, 95% CI=1.21–3.13). There was a significant interaction between high tHcy and aspirin use (OR=0.57, 95% CI=0.36–0.91), but not between high tHcy and B-vitamin use (OR=0.80, 95% CI=0.26–2.46). The analyses were adjusted for smoking status, Charlson index and use of antidepressants. The results of this study indicate that older men with high tHcy who use aspirin have lower risk of depression, and suggest that antiplatelet therapy may be an effective preventive or management strategy for these cases. Randomized trials are required to confirm the antidepressant effect of aspirin in people with high tHcy.

Aspirin decreases the risk of depression in older men with high plasma homocysteine

Ухудшение депрессивной симптоматики у группы больных в исследовании дулоксетина

New research shows that while many antidepressants help most people who take them, a small group of people who take them will actually feel more depressed than if they had just been taking a placebo or sugar pill.

 Some People Feel Worse on Antidepressants Like Cymbalta

Do Antidepressants Make Some People Worse?

Ещё одно неудачное исследование антидепрессанта нового механизма действия

On 8 November, Targacept, a drug company based in Winston-Salem, North Carolina, announced that TC-5214 had performed no better than placebo in one of four phase III trials. The results are a disappointment to clinicians eager for an innovative antidepressant.

TC-5214 is a form of mecamylamine, a blood-pressure drug introduced in the 1950s. It targets nicotinic α4β2 receptors (see ‘Mixed signals’), which normally receive chemical signals from the neurotransmitter acetylcholine. Because excess acetylcholine has been linked to major depression, blocking these signals might relieve the condition.

 Depression drug disappoints

Результаты исследования антидепрессанта тройного действия

A paper just out reveals that the snappily-named GSK372475 doesn't work and has lots of side effects. It's a report of two clinicals trials in which Glaxo's contender was pitched against placebo and against older antidepressants in the treatment of depression.

Another Antidepressant Bites The Dust

Антидепрессивная активность клавулановой кислоты не подтвердилась

The randomized, double-blind, placebo-controlled study compared two doses of Serdaxin, 0.5 mg and 5 mg, to placebo over an 8-week treatment period. Results from the study did not demonstrate Serdaxin's efficacy compared to placebo measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Rexahn Pharmaceuticals Announces Phase II Results for Serdaxin as Treatment for Major Depressive Disorder

Предупреждение нежелательных эффектов лекарственных препаратов в психиатрии

How to prevent adverse drug events

Назначение антидепрессантов при депрессивной симптоматике в рамках деменций не целесообразно

Antidepressants may provide little benefit but appear to increase adverse side effects in individuals with dementia and comorbid depression, suggesting that clinicians should reconsider use of these agents in this population, new research suggests.

Antidepressants of Little Use in Dementia Patients

Монотерапия антидепрессантами (STAR*D vs CO-MED)

Perhaps the HAM-D as administered across the CO-MED sites did not adequately capture the element of symptom severity most relevant to the emergence of clear drug effects. The CO-MED study group contained far fewer subjects with melancholia than did either of the groups of Blier et al., and depressed patients with melancholic features have been shown to have higher severity ratings on global and other symptom-based measures in comparison to those without melancholia, despite having nearly identical HAM-D scores (9). Group differences were only somewhat larger in the CO-MED subset with melancholic features than in the patients without them. The performance of melancholia as a response predictor, though, varies considerably by how its components are defined and applied (10), and the CO-MED report does not state how melancholic symptoms were assessed. The relative scarcity of melancholia in the CO-MED patients nevertheless indicates a correspondingly lower severity level on some dimension.

A particularly striking feature of the CO-MED study group is the coexistence of the absence of treatment resistance, as specified by the entry criteria, and a high rate of chronicity. Although none of the participants had had an adequate monotherapy trial of an FDA-approved antidepressant within the current episode, over one-half of the group had a depressive episode that had been fully syndromal for at least the preceding 2 years. Why had they not undergone even one adequate antidepressant trial before the CO-MED effort came to pass? Whatever the answer, it seems likely that the average interval between episode onset and the receipt of first treatment was quite long. A number of prospective studies of major depressive disorder have shown the no-treatment interval to be as robust a predictor of poor outcome with treatment as neuroticism (11). Why this is so is a matter of speculation, but the measure's association with poorer treatment response generally may well have narrowed differences between the regimens applied here.

The Search for Improved Antidepressant Strategies: Is Bigger Better?

Комбинации антидепрессантов не превосходят по эффективности монотерапию антидепрессантом

The first group took escitalopram (a selective serotonin reuptake inhibitor, or SSRI, brand name Lexapro) and a placebo; the second group received the same SSRI along with bupropion (a non-tricyclic antidepressant, brand name Wellbutrin); and the third group took two different antidepressants: venlafaxine (a tetracyclic antidepressant, Effexor) and mirtazapine (a serotonin norepinephrine reuptake inhibitor, Remeron).

After 12 weeks of treatment, all three groups showed similar remission and response rates: 39 percent, 39 percent and 38 percent, respectively, for remission; response rates were approximately 52 percent in all three groups. After seven months, remission and response rates remained similar in all three groups, but side effects were more frequent in the third group.

Two Antidepressants Appear No Better Than One

НПВС могут снижать эффективность СИОЗС

They then confirmed these effects in a human population. Depressed individuals who reported anti-inflammatory drug use were much less likely to have their symptoms relieved by an antidepressant than depressed patients who reported no anti-inflammatory drug use.

The effect was rather dramatic since, in the absence of any anti-inflammatory or analgesic use, 54 percent of patients responded to the antidepressant, wheh success rates dropped to approximately 40 percent for those who reported using anti-inflammatory agents.

Anti-Inflammatory Meds Can Reduce Antidepressant Effectiveness

Блокирование 5-HT7 рецепторов как потенциальный механизм быстрого антидепрессивного эффекта

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT7) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

Справочная информация по смене антипсихотиков, антидепрессантов и комбинированию нормотимиков

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Оксибутинин в качестве корректора гипергидроза вызванного приёмом антидепрессантов

Patient A is a 59-year-old man with a history of recurrent episodes of panic disorder, for which he had used paroxetine, venlafaxine, and escitalopram as well as high doses of oxazepam in the past. He was admitted to the hospital because of a severe depressive episode with suicidal ideation. The depression was successfully treated with clomipramine, 100 mg/day, which was effective for the treatment of panic attacks as well. Although he sweated all over his body, he was willing to continue clomipramine monotherapy after discharge. Lowering the dosage did not change the situation, nor did treatment with cognitive-behavioral therapy. Finally, a trial with oxybutynin, 2.5 mg b.i.d., relieved the hyperhidrosis completely, without any side effects.

Patient B is a 60-year-old man with recurrent severe depressive episodes with psychotic symptoms and agitation. Typical for his disorder are the rapid onset of relapse and the severity of agitation, which in the past required hospitalization and seclusion. In the latest episode he was treated with clomipramine, 75 mg/day, and olanzapine, 15 mg/day, but he suffered from severe hyperhidrosis. A switch from olanzapine to haloperidol did not change the hyperhidrosis. Later, 800 mg/day of lithium was successfully added for the treatment of his depressive symptoms. Oxybutynin, 5 mg t.i.d., was added to his treatment and relieved his hyperhidrosis without side effects.

There are several preferential strategies to treat hyperhidrosis, such as lowering the dosage or altering the dosing schedule, changing clothing or food habits, or regulating anxiety (2). In the present two cases, these strategies were unsuccessful and oxybutynin maintenance treatment was introduced. With its rapid, short-term effect (within an hour), oxybutynin could also be considered "as needed" in specific social situations. One should be careful in dosing to avoid anticholinergic side effects such as constipation, urinary retention, and blurred vision. Although placebo-controlled research is necessary, the cases reported here suggest that adding oxybutynin to antidepressants can be a simple and effective treatment option for hyperhidrosis.

Oxybutynin for Antidepressant-Induced Hyperhidrosis