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

Индивидуальные предпочтения в фармакотерапии среди врачей-психиатров

BACKGROUND:
Psychiatrists' preference for certain medications is not only determined by their efficacy and side effect profile but may also depend on the psychiatrists' beliefs about specific therapeutic effects based on their own observation and experience. We aimed to evaluate which antipsychotic or antidepressant drugs psychiatrists would prefer for themselves, their partners and children in case of a mental illness.
SUBJECTS AND METHODS:
The study was conducted among psychiatrists in Serbia. The sample consisted of 90 psychiatrists who were asked to complete the questionnaire about their drug selection in hypothetical situations of becoming ill with schizophrenia or depression or these conditions occurring in their partners and children.
RESULTS:
In case of schizophrenia, risperidone was the first choice made by most psychiatrists for themselves, their partners or children, followed by clozapine, haloperidol and olanzapine. In case of depression, SSRIs and SNRIs were generally favored, with sertraline and escitalopram being the preferred medications for psychiatrists, partners and their children. With regards to depression, 82.3% of participants would opt for an antidepressant as monotherapy or in combination, but 13.3% would opt for anxiolytic monotherapy. The preferred doses were slightly lower than the recommended ones, especially for antipsychotic agents.
CONCLUSIONS:
Most psychiatrists would take or administer atypical antipsychotics or SSRIs as the first choice for themselves, their partners or children. These preferences are mostly in accordance with current treatment guidelines, but there is still room to narrow the gap between guideline recommendations and psychiatrists' medication choices in personally meaningful situations.

 Psychiatrists' psychotropic drug prescription preferences for themselves or their family members.

Потенцирование антидепрессивного действия сертралина целекоксибом

Background
It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD).
Methods
In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale—17 items (Ham-D) score ≥ 18 were randomly assigned to either celecoxib (200 mg twice daily) or placebo in addition to sertraline (200 mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6.
Results
The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI) = 0.42(0.30 to 0.55) pg/ml, t(35) = 6.727, P < 0.001) as well as Ham-D scores (mean difference (95%CI) = 3.35(1.08 to 5.61), t(38) = 2.99, P = 0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P = 0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r = 0.378, P = 0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r = 0.673, P < 0.001).
Limitations
We did not measure other inflammatory biomarkers.
Conclusions
We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant

 Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: Randomized double-blind placebo-controlled study

Фармакогенетика СИОЗС, ассоциации между полиморфизмом CYP2D6 и CYP2C19 и ответом на терапию антидепрессантом

An investigation of MEDLINE and other database resources was carried out to summarize the research conducted between 1970 and 2003 in the role of CYP2D6 genetics on SSRI dose exposure.^[2] Area-under-the-concentration curve (AUC) values of 5 SSRIs in poor metabolizers, intermediate metabolizers, and extensive metabolizers as a measure of bioavailability were collected. Dose adjustments were then calculated to compensate for variability in CYP2D6 metabolizer status in white patients. On the basis of metabolizer phenotype, the following dose adjustments were extrapolated for extensive vs poor metabolizers: 33%-129% for fluvoxamine, 66%-114% for paroxetine, 56%-119% for fluoxetine (including the AUC of its active metabolite), 98%-101% for citalopram, and 99-100% for sertraline. A dose adjustment of 130% for paroxetine was extrapolated for ultrarapid metabolizers.

However, the study authors concluded that dose adjustments that are based on CYP2D6 could not be recommended for SSRIs for various reasons. They noted the limited data from multiple dosing, which more accurately reflects the clinical situation; the unknown effect of saturation kinetics of some SSRIs (eg, paroxetine and fluvoxamine); and the long-term effect of inhibition of CYP2D6 by some SSRIs (eg, fluoxetine, fluvoxamine, and paroxetine) when given in chronic treatment regimens. Thus, basic human pharmacokinetic data do not strongly support routine clinical use of CYP2D6 testing.

Another study scanning 1200 Web-based articles between 1966 and 2006 for treatment of major depression found no consistent association between CYP2D6 genotype and SSRI metabolism, efficacy, or risk for side effects.^[3]Although 2 studies showed greater nonresponse to SSRIs among ultrarapid metabolizers relative to the general population, the data were inconsistent across other studies. The study authors concluded that there is no established association between plasma drug concentration and SSRI drug response at standard doses.

Finally, a study of SSRI drug response and tolerability in 1953 patients enrolled in the Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) study also showed no significant association between CYP2D6 variants and citalopram response, remission, or tolerability when comparing extensive metabolizers with poor metabolizers. However, the study design included numerous concomitant medications with unknown confounding effects.^[4]

The complexity derived from interaction between multiple CYP enzymes was highlighted in a study of the impact of extensive and poor metabolizer status for CYP2D6 and CYP2C19 on the SSRI citalopram. Researchers showed that the AUC for citalopram correlated with the combined CYP2D6/CYP2C19 metabolizer status.^[5] For example, individuals with CYP2D6 extensive metabolizer/CYP2C19 poor metabolizer status showed significantly higher citalopram AUC compared with extensive/extensive metabolizer or poor/extensive metabolizer carriers. Because citalopram metabolism is preferentially catalyzed by CYP2C19 over CYP2D6, consideration of more than 1 genetic variant may be necessary to guide medication dosing decisions.

Pharmacogenomics of SSRIs: Clinical Implications

Сертралин

Sertraline Hydrochloride Tablet

STAR*D

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission.
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35


An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed. Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.

The Role of L-methylfolate in Depressive Disorders

Сертралин+налтрексон

More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence

Антидепрессанты при БАР

"Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder"

"One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,14 but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,13 paroxetine,12,13,15 and bupropion12 yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone."

"The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year."

"Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with."

Antidepressants in bipolar disorder: 7 myths and realities

Микседематозная кома вызванная комбинацией арипипразола и сертралина

Myxedema Coma Associated with Combination Aripiprazole and Sertraline Therapy
Chelsea O Church, PharmD BCPS

Associate Professor of Pharmacy Practice, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK

Erin C Callen, PharmD BCPS

Associate Professor of Pharmacy Practice, College of Pharmacy, Southwestern Oklahoma State University

Reprints: Dr. Church, Department of Pharmacy Practice, Southwestern Oklahoma State University College of Pharmacy, Pasteur Medical Building, Pharmacy Education, 1111 North Lee, Ste. 241, Oklahoma City, OK 73103, fax 405/601-1201, chelsea.church@swosu.edu

OBJECTIVE: To describe a case of myxedema coma (MC) associated with combination aripiprazole and sertraline therapy.

CASE SUMMARY: A 41-year-old male presented to the emergency department with confusion, right-sided numbness and tingling, slurred speech, dizziness, and facial edema. His blood pressure was 160/113 mm Hg, with a pulse of 56 beats/min and temperature of 35.4 °C. Initial abnormal laboratory values included creatine kinase (CK) 439 U/L; serum creatinine 1.6 mg/dL; aspartate aminotransferase 85 U/L; and alanine aminotransferase 35 U/L. Repeat cardiac markers revealed an elevated CK level of 3573 U/L with a CK-MB of 24 ng/mL. Thyroid function tests showed thyroid-stimulating hormone 126.4 µIU/mL and free thyroxine 0.29 ng/dL. Home medications of unknown duration were sertraline 200 mg and aripiprazole 20 mg daily. He was admitted to the intensive care unit and initially treated with intravenous levothyroxine and dexamethasone. By hospital day 4, the patient was clinically stable and discharged to home.

DISCUSSION: Myxedema coma, the most significant form of hypothyroidism (HT), is a rare but potentially fatal condition. The known precipitating causes of MC were ruled out in this patient, which left his home medications as the likely cause. Cases of HT caused by certain atypical antipsychotics and antidepressants are found in the literature, but none was reported with aripiprazole therapy. There are also no reported cases of sertraline or aripiprazole inducing MC. Use of the Naranjo probability scale indicates that the combination of aripiprazole and sertraline was a probable inducer of MC in this patient.

CONCLUSIONS: Due to the widespread use of psychotropic medications, clinicians should be reminded of the rare, yet life-threatening, occurrence of MC when treating patients, especially with combination therapies such as sertraline and aripiprazole.

Myxedema Coma Associated with Combination Aripiprazole and Sertraline Therapy

Anxiety Disorders in Children and Adolescents. Early Identification and Evidence-Based Treatment

Anxiety Disorders in Children and Adolescents

Комбинация сертралина с оланзапином в терапии психотической депрессии

At the conclusion of the 12-week trial, investigators found that treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio, 1.28; 95% confidence interval, 1.12 – 1.47; P < .001) and that 49% of subjects in the combination therapy group were in remission at their last assessment vs 23.9% of those treated with olanzapine alone.

In addition, the study showed that combination therapy was comparably superior in both younger and older age groups. Although both age groups experienced significant increases in cholesterol and triglyceride concentrations, statistically significant increases in glucose occurred in younger adults.

Further, whereas both age groups experienced weight gain, younger adults gained significantly more weight than their older counterparts — a mean gain of 6.5 vs 3.3 kg.

The study findings suggest that combination therapy is effective and offers physicians and their patients a viable alternative to electroconvulsive therapy, which is generally considered the treatment of choice for this condition but is not without challenges.

The researchers note that although bilateral electroconvulsive therapy has a response rate of 87% when administered in academic centers, the response when delivered in the community setting is much lower, ranging from 30% to 47%. Further, they add, pharmacological treatment may be more practical and less stigmatizing for patients.

STOP-PD: Combination Therapy With Sertraline Plus Olanzapine Effective in the Treatment of Psychotic Depression

A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression

Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy ({chi}21 = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001).

A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression