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

Перерыв в лечении ГТР венлафаксином не осложняет достижения ремиссии

After study procedures were completed, the researchers offered venlafaxine XR for six months to the subjects who had relapsed after being switched from venalfaxine treatment to a placebo. Twenty-seven subjects accepted the offer. Preliminary results indicated that they again improved to the same degree as patients who had been on it for 12 months. “These results surprised us,” Rickels said. “If this finding can be repeated, it would mean that patients who are for at least six months on venlafaxine XR could go off medication until the symptoms return.”

Extended GAD Treatment Keeps Relapse Rates Low

Длительность лечения тревожного расстройства

Relapse rates after 12 months of venlafaxine XR treatment were 6.7% for patients who were taking venlafaxine XR for the full 18 months, 20.0% for patients taking placebo for 12 months (months 6 to 18), and 32.3% for placebo patients who switched at month 12 to placebo (P < .14).

The study also found that patients treated with venlafaxine XR for 12 months before being shifted to placebo experienced a lower relapse rate (32.4%) than patients shifted to placebo after taking venlafaxine XR for only 6 months (53.7%; P < .03).

Chronic Anxiety Requires Long-Term Treatment to Prevent Relapse

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

Сравнительная таблица: дулоксетин и венлафаксин

"Venlafaxine (Effexor, Effexor XR) has the flexibility of being an SSRI at lower doses (75 mg/day), affecting the reuptake of serotonin, and an SNRI at higher doses (150-225 mg/day). It also very weakly blocks the reuptake of dopamine at very high doses (above 350 mg/day).

Duloxetine (Cymbalta) is a strong, balanced inhibitor of both norepinephrine and serotonin reuptake.

Duloxetine differs from venlafaxine in that it is comparatively more noradrenergic। Venlafaxine has a 30-fold higher affinity for serotonin than for norepinephrine while duloxetine has a 10-fold selectivity for serotonin6. Approximate potency ratios (5-HT:NE) are 1:10 for duloxetine, and 1:30 for venlafaxine."

Brief comparison table

	Venlafaxine (Effexor)	Duloxetine (Cymbalta)
Generic name	Venlafaxine hydrochloride	Duloxetine hydrochloride
Brand name/Manufacturer	Wyeth	Eli Lilly
FDA approval date	1993	2004
Active Metabolite	O-Desmethylvenlafaxine	5-hydroxy-duloxetine 6-methoxy-duloxetine
Half-life	4 (11 for O-desmethylvenlafaxine)	12 hours (range 8 to 17 hours)
Time to steady-state	3 days	3 days
Bioavailability, %	45	50
Potential for interactions	Has one of the most favorable drug-interaction profiles4 Weak or negligible inhibitor of CYP isozymes (CYP2D6, CYP1A2, CYP2C19, and CYP3A4)	Moderate inhibitor of CYP2D6, has the potential to interact with other drugs that are also metabolized by this cytochrome P450 system
Generic avalability	Yes	No
FDA Pregnancy Category	C	C
Most common side effects	nausea headache somnolence dizziness insomnia nervousness dry mouth anorexia sweating abnormal ejaculation constipation impotence	nausea somnolence headache dry mouth dizziness insomnia fatigue constipation diarrhea decreased appetite vomiting erectile dysfunction
Mode of action	Serotonergic at lower doses, modest noradrenergic effects at higher doses (> 250 mg/day)	Strong, balanced inhibitor of both norepinephrine and serotonin reuptake

Antidepressants Comparison: Effexor versus Cymbalta

"

In a study by Bymaster and colleagues it was found that duloxetine inhibited binding to the human norephinepherine (NE) and serotonin (5-HT) transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively.

Thus, duloxetine more potently blocks serotonin and norephinepherine transporters in vitro and in vivo than venlafaxine,^[23] arguably making it the most potent of all commercially available SNRIs. Duloxetine and venlafaxine have not been measured against milnacipran."

Duloxetine

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

Антидепрессанты и катаракта

Researchers found patients taking SSRIs were overall 15 percent more likely to be diagnosed with cataracts or to have cataract surgery.

The degree of risk among specific and different types of SSRIs varied considerably. Taking fluvoxamine (Luvox) led to a 51 percent higher chance of having cataract surgery, and venlafaxine (Effexor) carried a 34 percent higher risk.

No connection could be made between fluoxetine (Prozac), citalopram (Celexa), and sertraline (Zoloft) and having cataract surgery.

Some Antidepressants Related to Cataract Risk

Combining Antidepressant Medications: A Good Idea?

SNRIs Anti-depressants

Trazodone (Desyrel) inhibits serotonin reuptake in addition to blocking certain types of serotonin, norepinephrine, and histamine receptors. Histamine is a both a biological chemical involved in immune responses as well as a neurotransmitter. In low doses, Trazodone can be used as a sleep aid, especially for people who experience insomnia as part of their depression. Side effects of Trazodone include: allergic reactions, irregular heartbeat, prolonged and painful erection, drowsiness, fatigue, lethargy (exhaustion), psychomotor retardation (slow movements), lightheadedness, dizziness, difficulty concentrating, confusion, impaired memory, disorientation, excitement, agitation, anxiety, tension, nervousness, restlessness, insomnia, nightmares, anger, hostility and, rarely, hypomania, visual distortions, hallucinations (sensing things that aren't really there), delusions (false, fixed beliefs), and paranoia (suspicious fear).

Buproprion (Wellbutrin) is often a first choice treatment for Major Depressive Disorder. This medication is just as effective as SSRIs in treating depressive symptoms, with less risk of weight gain and sexual side effects. In addition to serotonin and norepinephrine, buproprion also inhibits dopamine reuptake. The most common side effects of buproprion are dry mouth, constipation, headaches, and insomnia. Care must be taken when using buproprion at higher doses, as it has been known to cause seizures.

Venlafaxine (Effexor) is often used for the treatment of depressive illnesses, but large numbers of studies demonstrating treatment success are lacking. In addition to inhibiting serotonin reuptake, venlafaxine inhibits norepinephrine and dopamine reuptake. Venlafaxine does not interfere with other brain chemicals, which makes it less "messy" and more powerful than other antidepressants. Some evidence suggests that venlafaxine relieves depressive symptoms more quickly than other medications with fewer side effects, and that it can be combined safely with other medications. However, more research is necessary to substantiate these claims.

Nefazodone (Serzone) inhibits serotonin reuptake by blocking a particular type of serotonin receptor. Serzone is sedating, and is useful for relieving anxiety and severe insomnia. Furthermore, sexual side effects are mild, if any. Unfortunately however, nefazodone is a strong inhibitor of liver enzymes and should be used cautiously. Many medications are metabolized in the liver, and functional liver enzymes are essential to proper liver functioning and overall health.

Mirtazapine (Remeron) blocks serotonin and norepinephrine reuptake. Mirtazapine is sedating, and has the disagreeable side effect (for most) of weight gain in comparison with other SSRIs. Although few studies clearly demonstrate Mirtazapine's usefulness in treating unipolar depression, this medication may be a good option for people who have experienced significant weight loss during their depressive episodes.

Antidepressants for Major Depression - Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRI)

"Why does this matter? Because the two scales used to rate depression in this study, the Hamilton Scale and the Montgomery-Asberg Scale, both count reduced appetite and sleeplessness as symptoms of depression. If you're on mirtazapine, you're unlikely to have either problem - you'll be more worried about the exact opposite, insatiable hunger and drowsiness. So mirtazapine could reduce your total score on these scales even if it didn't change your mood. I have no idea to what extent this is a factor in these results, but it could be important."

Two Drugs Are Better Than One?

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

Anxiety Disorders in Children and Adolescents

Антидепрессанты короткого действия в терапии БАР с быстрой сменой фаз

"I have found that in bipolar patients with extreme diurnal variation of mood (characterized by severe a.m.-hour depression followed by significant brightening in the evening), the non-time-release preparations of medications, such as bupropion and venlafaxine, given in low doses in the a.m. hours only can be very helpful and less likely to cause manic switching. Conversely, the long-acting preparations of the same medications tend to cause a reversal of diurnal variation, with improvement in the a.m. hours and agitation in the p.m. hours. It might turn out that short half-life reuptake inhibitors have a place in treating bipolar depression. Other relatively short-acting agents, such as atomoxetine, may also fall into this category."

The Use of Short Half-Life Antidepressants in the Treatment of Bipolar Depression