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

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

Treatment of Sexual Side Effects: Antidotes

Treatment of Sexual Side Effects: Antidotes

A variety of antidotes have been reported to treat SSRI-induced sexual dysfunction effectively; however, virtually all the data on these agents are derived from open case reports and case series. Insofar as sexual function improvement may be responsive to placebo effects, it is impossible to estimate the true efficacy of these antidotes.[27]

Most of these antidotes either have serotonin-blocking properties (especially 5HT-2 antagonistic effects) or augment catecholamine activity, especially that of dopamine. The antiserotonergic antidotes are cyproheptadine, buspirone, nefazodone, and mianserin. Medications enhancing dopaminergic tone include amantadine, bupropion, and stimulants, with yohimbine showing noradrenergic effects. Among the reported antidotes, the only 2 without antiserotonergic effects or catecholaminergic activity are gingko biloba and urecholine.

Cyproheptadine is an antihistamine with antiserotonergic properties that has been reported for over a decade to reverse antidepressant-induced sexual dysfunction. Only case reports and case series attest to its efficacy.[13,42-44] Effective doses range from 2mg to 16mg. In the most recent and largest case series, 12 of 25 patients described improvement in sexual function when treated with cyproheptadine (mean dose, 8.6mg).[13] Anorgasmia is the sexual side effect most often reported to be alleviated by cyproheptadine. Cyproheptadine is effective when taken either on an as-needed basis (typically, 1 to 2 hours before intercourse) or on a regular basis.

However, cyproheptadine's utility is often limited by its potential side effects. Excessive sedation and the reversal of the therapeutic effect of the antidepressant are major problems that limit its usefulness. Effectively treated depression and bulimic symptoms have been reported to reemerge soon after cyproheptadine was started.[42,45-48] This reversal of therapeutic effects is itself reversible upon discontinuation.

Buspirone is a serotonin-IA partial agonist typically prescribed to treat persistent anxiety. One case series reported that buspirone reversed both decreased sexual interest and orgasmic dysfunction caused by SSRIs.[49] Most patients using buspirone to treat sexual dysfunction take it daily. The dosage is the same as that used for anxiety (15mg to 60mg daily). The mechanism of action of buspirone in treating sexual dysfunction may be reduction of serotonergic tone via stimulation of presynaptic autoreceptors or the alpha-2 antagonist effects of one of buspirone's major metabolites, 1-pyrimidinylpiperazine.

Nefazodone and mianserin are antidepressants with strong postsynaptic blocking properties. In one case report, nefazodone 150mg taken 1 hour prior to sexual activity completely reversed sertraline-induced anorgasmia.[50] Mianserin, an antidepressant with 5HT-2 and alpha-2 adrenergic antagonist properties, is available in many countries but not in the US. It has been reported to reverse serotonin reuptake inhibitor-induced sexual dysfunction in 9 of 15 patients.[51] Mirtazapine is similar in its biological activity to mianserin and might also be effective in reversing sexual side effects. No case reports or case series have yet been published attesting to this, although clinicians have described such an effect. The putative capacity of mianserin and mirtazapine to reverse sexual side effects can be attributed either to their serotonergic activity or presynaptic alpha-2 activity.

Amantadine, a dopamine agonist, is used both as an antiviral agent and as a treatment for Parkinson's disease. It has been shown in a number of small case series to reverse anorgasmia.[13,52-54] Reported effective doses have ranged between 100mg to 400mg taken either on a daily or as-needed basis. In the most recent case series, 8 (42%) out of 19 patients with SSRI-induced sexual dysfunction improved with amantadine 200mg daily.[13] Given dopamine's consistent effect as a neurotransmitter involved in sexual arousal, a number of other dopamine agonists have been explored as treatments for sexual side effects.[2,55,56]

Bupropion is another commonly touted antidote for SSRI-induced sexual dysfunction.[57,58] It is assumed that the mechanism of action by which bupropion reverses sexual side effects is its weak dopamine agonism. The evidence for bupropion's efficacy is scant, except for unpublished, anecdotal reports, one case report,[57] and a case series[58] in which 31 (66%) of 47 patients showed improvement when bupropion was added to the regimen along with the serotonergic antidepressant. Most patients (18/31) with a successful outcome responded to as-needed use of bupropion 75mg to 150mg. Libido, arousal, and orgasmic difficulties were all effectively reversed. Fifteen percent of treated patients stopped taking bupropion because of its stimulation side effects. It is unclear whether bupropion doses need to be somewhat lower than usual when added to fluoxetine or paroxetine, to compensate for pharmacokinetic interactions resulting in increased bupropion levels.[59]

Stimulants, such as methylphenidate, D-amphetamine, and pemoline, are reported to reverse a variety of sexual side effects caused by SSRIs or MAOIs.[60-62] Low doses of 10mg-25mg of methylphenidate or D-amphetamine have been effective. One should add stimulants to an MAOI with extreme caution because of the risk of a hypertensive episode. However, use of an MAOI/stimulant combination has been shown to be safe in a case series.[63] SSRI/stimulant combinations show no similar risks.

Yohimbine is available with or without a prescription (and with unclear purity) in health food stores. It is an alkaloid from the bark of Corynanthe yohimbi (family, Rubiaceae) and has been used for decades to reverse erectile dysfunction.[64-66] Its efficacy in treating sexual dysfunction may be associated with its ability to block presynaptic alpha-2 adrenergic sites, leading to enhanced adrenergic tone.[65] A variety of sexual side effects have been reported to be alleviated by yohimbine in doses ranging from 2.7mg to 16.2mg daily, prescribed either on a regular 5.4mg 3 times daily basis or on an as-needed basis with single doses up to 16.2mg.[13,67-69] In the largest case series, 17 (81%) of 21 patients showed improvement of sexual side effects when treated with yohimbine (mean dose, 16.2mg).[12]

Typical side effects associated with yohimbine include anxiety, nausea, flushing, urinary urgency, and sweating. Yohimbine has been the subject of the only double-blind, placebo-controlled study to evaluate treatment of sexual dysfunction occurring as a drug side effect.[27] Unfortunately, the placebo effect was marked, showing a minimal drug-placebo difference with yohimbine given at a dose of 5.4mg 3 times daily. Yohimbine is also available in lower potency without a prescription. The purity, potency, and safety of these preparations, however, are unknown.

Bethanechol is a cholinergic agonist that has occasionally been useful in reversing sexual dysfunction associated with TCAs and MAOIs.[70-73] Typical doses are 10mg to 20mg as needed or 30mg to 100mg daily in a divided dose. Potential side effects with bethanechol include diarrhea, cramps, and diaphoresis. No reports have evaluated or suggested the efficacy of bethanechol for treating SSRI-induced sexual side effects.

Gingko biloba is an herbal extract reported to reverse a variety of sexual dysfunctions associated with antidepressants. Information about gingko's ability in this regard is derived from the experience of 1 clinician presenting a large case series.[74] The response rate was greater than 80%, with doses ranging from 60mg twice daily to 120mg twice daily (mean daily dose, 207mg). Reported side effects include gastrointestinal upset, lightheadedness, and stimulation effects. Because gingko may inhibit platelet-activating factor, caution should be used in considering its use by any patient with a bleeding diathesis. The mechanism by which gingko might alleviate sexual dysfunction is unknown.

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