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

Связь вариаций CYP2C19 с риском аритмий при приёме циталопрама и эсциталопрама

Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.

CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation

Комбинация эсциталопрама с арипипразолом в терапии коморбидной депрессии алкогольной зависимости

 The effective treatment of depression has been reported to reduce the severity of alcohol use, potentially reflecting improvements in common brain reward circuits. We hypothesized that augmentation therapy of escitalopram with aripiprazole would improve depressive symptoms as well as reduce craving for alcohol and cue-induced brain activity in patients with co-morbid alcohol dependence and major depressive disorder, compared with treatment with escitalopram alone. Thirty-five subjects with major depressive disorder and alcohol dependence were recruited and randomly assigned into 17 aripiprazole + escitalopram and 18 escitalopram only groups. At baseline and following six weeks of treatment, symptoms of depression, craving for alcohol and brain activity were evaluated. During the six week treatment period, Beck Depression Inventory and clinical global index-severity (CGI-S) scores decreased in both the aripiprazole + escitalopram and escitalopram only groups. In addition, following the treatment period, the Korean alcohol urge questionnaire scores in the aripiprazole + escitalopram group were reduced from 23.3±8.4 to 14.3±4.9, compared with those of the escitalopram group of from 21.6±8.4 to 19.3±7.1 ( F=13.1, p < 0.01 ). The activity within the anterior cingulate was increased in response to the presentation of alcohol drinking scenes following treatment in the aripiprazole + escitalopram group. The change of brain activity within the left anterior cingulate gyrus in all patients with co-morbid alcohol dependence and major depressive disorder was negatively correlated with the change in craving for alcohol. These findings suggest that the effects of aripiprazole on anterior cingulate cortex might mediate the successful treatment of alcohol dependence in patients with major depressive disorder.

Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: Clinical and neuroimaging evidence

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.

Предиктор эффективности терапии эсциталопрамом

A recent Loyola study found that the blood test for a protein called vascular endothelial growth factor (VEGF) could help predict successful treatment. The researchers found that among depressed patients who had higher than normal levels of VEGF, more than 85 percent experienced partial or complete relief after taking escitalopram (Lexapro).

 Blood Test May Predict Antidepressant Effectiveness

Интраназальный окситоцин в дополнение к эсциталопраму в терапии депрессии

Oxytocin (OT) is, first, a hormone synthesized in the hypothalamus and released by the neurohypophysis, but OT is also involved in the regulation of emotions, and OT receptors are distributed in various brain regions, including the limbic system and amygdala. There is much data suggesting a role for OT as an endogenous antidepressant/anxiolytic hormone and there is support for the idea that stimulation of OT receptors inhibits the hypothalamo-pituitary-adrenal (HPA) axis. The pathophysiology of stress-related diseases, such as depression or anxiety disorders, includes both endogenous/genetic predisposing factors and a dysregulated response to stress, and efficiency of antidepressants involves normalization of HPA-axis abnormalities.

Case Report

RX is a 38-year-old man with a 15-year history of major depressive disorder without psychotic features. His depression severely worsened over a 5-year period despite various antidepressant treatments (tricyclics, serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors). He also received benzodiazepines and amisulpride without clinical success. His current treatment involves escitalopram 20 mg. After he gave full informed consent, intranasal synthetic OT (Syntocinon®, 1 puff per nostril each with 4 U.I., twice daily; Novartis Pharmaceuticals Corporation, Switzerland) was added. Initial severity of depression was scored at 17 on the Hamilton Rating Scale for Depression (Ham-D), and anxiety reached 57 on the Spielberger State-Anxiety Inventory (STAI–A). One week after OT initiation, his Ham-D score decreased to 11, and the STAI–A score to 49. At this time, the patient bought a car after several months of hesitancy. He contracted a loan and explained that he was offered good buying conditions. One week later, the patient was very much improved; his HAM-D score dropped to 2, and his STAI–A to 37. Unfortunately, Syntocinon® was stopped after 1 week because the patient missed the visit. After this period, the patient was much worse. Intranasal OT was then delivered at the dose of 36 UI per day in addition to escitalopram, 20 mg. His symptoms improved after 7 days (Ham-D: 5; STAI–A: 48). At the same time, he was very affected by the [bankruptcy] of his [step-]father, who raised him. One week later, he offered to install hardware [electronic equipment] in his parent's house. On The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), he scored at higher levels, going from 1 to 4 by the end of the study.

Discussion

This is the first trial of OT as an adjunct to antidepressant in major depression. Our case report suggests that OT instillation significantly improves mood and anxiety. OT was already shown to reduce responses to social stress,1 to increase trust,2 and improve "mind-reading" in humans.3 It is possible that the efficacy of SSRIs in restoring interest in social interactions is due, in part, to their action on the reward circuit via the OT system.4 Further studies are needed to investigate the effects of OT or OT-receptor selective agonists in additional clinical models to promote the development of psychopharmacology targeting central OT receptors.

Intranasal Oxytocin as an Adjunct to Escitalopram in Major Depression

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

Применение эсциталопрама в дозах превышающих максимальные у больных с резистентной депрессией

Methods

This open-label, pilot study was designed to investigate the efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD). It was conducted in 60 primary care patients with MDD who had not responded to adequate treatment with citalopram. Patients were treated with escalating doses of escitalopram up to 50 mg for up to 32 weeks until they achieved remission (Montgomery-Asberg Depression Rating Scale [MADRS] (less than or equal to 8) or failed to tolerate the dose.
Results

Forty-two patients (70%) completed the study. Twenty-one patients (35%) achieved remission with 8 of the 21 patients (38%) needing the 50 mg dose to achieve remission. Median time to remission was 24 weeks and median dose in remission was 30 mg. No significant safety issues were identified although tolerability appeared to decline above a dose of 40 mg with 26% of patients unable to tolerate 50 mg. Twelve (20%) patients had adverse events leading to discontinuation. The most common adverse events were headache (35%), nausea, diarrhoea and nasopharyngitis (all 25%). Minor mean weight gain was found during the study, which did not appear to be dose-related. Half of the patients who completed the study chose to continue treatment with escitalopram rather than taper down the dose at 32 weeks.

Efficacy, safety and tolerability of escitalopram in doses up to 50 mg in Major Depressive Disorder (MDD): an open-label, pilot study

Терапия генерализованного тревожного расстройства

Studies comparing antidepressants with benzodiazepines in the treatment of GAD showed that although benzodiazepines work quickly, the antidepressants lower anxiety more effectively in the long term.[11] Antidepressants that have been approved by the United States Food and Drug Administration (FDA) for the treatment of GAD are extended-release venlafaxine,[12] duloxetine,[13] escitalopram,[14] and paroxetine.[15] Although not FDA approved, citalopram has also been found to be effective for the treatment of GAD.[16] Whereas benzodiazepines have been shown effective for shortterm anxiety, they may worsen depression, a common comorbidity of GAD, and cause other cognitive adverse effects such as sedation and anterograde amnesia. Individuals with a history of substance abuse or dependence should not use benzodiazepines, but patients with no such history rarely abuse these agents and can use them safely.[17] Buspirone and pregabalin also have proven efficacy for GAD.[18–21]

Table 1. Summary of Clinical Trials of Adjunctive Use of Atypical Antipsychotics for Treatment-Resistant Generalized Anxiety Disorder^a

Agent	Study Design	No. of Patients	Study Duration (wks)	Mean Daily Dose (mg)	Change in Assessment Score	Mean Weight Gain (lbs)b
Aripiprazole[30]	Open label	17	4.9	16.9	CGI-S: −1.6	NR
Aripiprazole[31]	Open label	10	9	NR	HAM-A: −20.6	7.1
Aripiprazole[32]	Open label	9	6	13.9	HAM-A: −12 CGI-I: 8 of 9 patients rated as much improved or very much improved	NR
Aripiprazole[33]	Open label	23	8	10.5	HAM-A: −6.7 CGI-S: −1	2.5
Olanzapine[34]	Randomized, controlled	21	6	8.7	HAM-A: olanzapine −7 vs placebo −3.9 (p=0.4) CGI-S: 67% of patients rated as not at all ill or borderline ill	11
Quetiapine[35]	Randomized, controlled	58	8	182	HAM-A: quetiapine −12.5 vs placebo −5.9 (p=0.002)	5.2
Quetiapine[36]	Randomized, controlled	22	8	120	HAM-A: quetiapine −2.6 vs placebo −0.3 (p=0.98)	2.7
Quetiapine[37]	Open label	40	12	386	HAM-A: −20.6	1.1
Risperidone[38]	Open label	16	8	1.12	HAM-A: −6.75 CGI-S: −1.53	3.9
Risperidone[39]	Randomized, controlled	40	5	1.1	HAM-A: risperidone −9.8 vs placebo −6.2 (p=0.034)	2.3
Risperidone[40]	Randomized, controlled	390	4	0.86	HAM-A: risperidone −9.26 vs placebo −9.12 (p=0.858) PaRTS-A: risperidone −8.54 vs placebo −7.61 (p=0.265)	2.65
Ziprasidone[41]	Open label	13	7	40	HAM-A: −11.2	0.2

HAM-A = Hamilton Rating Scale for Anxiety (lower scores indicate less severe symptoms of anxiety); CGI-S = Clinical Global Impressions-Severity (lower scores indicate less severe illness); CGI-I = Clinical Global Impression–Improvement; NR = not reported; PaRTS-A = Patient-Rated TroublingSymptoms for Anxiety.
^aAll atypical antipsychotic treatment was added to current antidepressant therapy.
^bIn patients who received the atypical antipsychotic.

Adjunctive Use of Atypical Antipsychotics for Treatment-resistant Generalized Anxiety Disorder

генетические предикторы усиления суицидальной идеации

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

предикторы эффективности антидепрессантов

A new medical test — called a biomarker test — appears to help predict a patient’s response to a specific antidepressant. The test is non-invasive, painless and fast, taking about 15 minutes. Six electrodes (which measure brain activity) are placed around the forehead and on the earlobes (the electrodes don’t hurt — they are only measuring devices).

Here’s what the study found:

Subjects were then randomly assigned to continue with escitalopram or were given a different drug. A total of 73 patients who remained on escitalopram were tracked for 49 days to see if their results matched the prediction of the ATR biomarker. The ATR predicted both response and remission with an accuracy rate of 74 percent, much higher than any other method available.

The researchers also found that they could predict whether subjects were more likely to respond to a different antidepressant, bupropion, also known as Wellbutrin XL.

Test Predicts Depression Medication Response