Влияние различных антидепрессантов на фазы сна

A clinical consequence of REM suppression can be a change in frequency and intensity of dreaming, as well as a pronounced exacerbation of intense, disturbing dreams related to “REM rebound” on discontinuation. Pulmonary specialists sometimes advocate use of an activating TCA such as protriptyline because it may help suppress REM sleep—when sleep apnea episodes may be accentuated—and also provide benefit for the daytime somnolence that many patients with sleep apnea experience.

The Effects of Antidepressants on Sleep

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

PHQ-9

Table 3. PHQ-9

1. Over the past 2 weeks, how often have you been bothered by any of the following problems?
	Not at all (0)	Several days (1)	More than half the days (2)	Nearly every day (3)
a. Little interest or pleasure in doing things
b. Feeling down, depressed, or hopeless
c. Trouble falling/staying asleep, sleeping too much
d. Feeling tired or having little energy
e. Poor appetite or overeating
f. Feeling bad about yourself -- or that you are a failure or have let yourself or your family down
g. Trouble concentrating on things, such as reading the newspaper or watching television
h. Moving or speaking so slowly that other people could have noticed. Or the opposite -- being so fidgety or restless that you have been moving around a lot more than usual
i. Thoughts that you would be better off dead or of hurting yourself in some way
2. If you checked off any problem on this questionnaire so far, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?
	Not difficult at all	Somewhat difficult	Very difficult	Extremely difficult

Table 4. Interpretation of PHQ-9 Results

Score/ Symptom Level	Treatment
0-4 No depression	Consider other diagnoses
5-9 Minimal	▪ Consider other diagnoses ▪ If diagnosis is depression, watchful waiting is appropriate initial management
10-14 Mild	▪ Consider watchful waiting ▪ If active treatment is needed, medication or psychotherapy is equally effective; consider function score in choosing treatment
15-19 Moderate	▪ Active treatment with medication or psychotherapy is recommended ▪ Medication or psychotherapy is equally effective
20-27 Severe	▪ Medication treatment is recommended ▪For many people, psychotherapy is useful as an additional treatment ▪ People with severe symptoms often benefit from consultation with a psychiatrist

Data from Kroenke K, Spitzer R. Psychiatr Ann. 2002;32:509-521.

A number of combinations have some benefit in selected patients, including:

• Lithium augmentation at stage 3 of STAR*D resulted in remissions in 15.9%.^[84] Lithium in combination with SSRIs and TCAs also has been effective in placebo-controlled studies, most involving small numbers of subjects. Such treatment requires monitoring of lithium levels, because there is a small difference between therapeutic and toxic levels.^[85]
• Thyroid hormone, and particularly triiodothyronine, has been studied for augmentation with the TCAs. In the STAR*D study, at step 3, augmentation with triiodothyronine led to a remission rate of 24.7%.^[84] Placebo-controlled studies have involved small numbers of subjects and have had mixed results.^[86]
• A heterocyclic-SSRI combination in 1 small study produced more rapid treatment onset and increased the likelihood of remission.^[87] In the study, a combination of fluoxetine and desipramine (a norepinephrine reuptake inhibitor) was more effective in achieving remission than either drug used as monotherapy: 53.8% for the combination, compared with 7.1% and 0%, respectively. However, such combinations can produce the serotonin syndrome, which is potentially life-threatening, and the dose of the heterocyclic must be adjusted using blood levels because SSRIs increase TCA levels through CYP-450 isoenzyme interactions (eg, fluoxetine increases the levels of desipramine 3- to 4-fold).^[88] Consequently, this augmentation strategy should rarely be considered in primary care.
• Mirtazapine has recently been evaluated in combination therapy with an SSRI (fluoxetine), an SNRI (venlafaxine), or bupropion.^[89] The investigators found that all 3 combinations were more effective than fluoxetine alone in achieving remission (52%, 58%, 46%, respectively, compared with 25%). In patients who responded, double-blind discontinuation resulted in relapse in about 40%. Of note, treatment was initiated with these combinations, rather than mirtazapine being used as an augmenting agent in those not initially responding.
• Methylfolate and folate have been used to augment SSRIs, resulting in increased rates of remission, particularly in women.^[90] The degree to which the response is due to folate deficiency, and whether methylfolate is of greater benefit due to its increased ability to cross the blood-brain barrier, are subject to further research.
• Antidepressants and hypnotics have been used together, with early improvement not only in sleep measures, but also in rates of depression remission.^[91]
• Stimulant drugs have been used as augmentation of heterocyclics or SSRIs.^[92] Of note, in individuals with comorbid medical illness, amphetamine stimulants should be used with caution, particularly if cardiac disease is potentially present.

Clinical and Pharmacologic Strategies to Achieve Remission in Depression

Эффективность антидепрессантов в лечении негативной симптоматики при шизофрении

Background

Treatment of negative symptoms in chronic schizophrenia continues to be a major clinical issue.

Aims

To analyse the efficacy of add-on antidepressants for the treatment of negative symptoms of chronic schizophrenia.

Method

Systematic review and meta-analysis of randomised controlled trials comparing the effect of antidepressants and placebo on the negative symptoms of chronic schizophrenia, measured through standardised rating scales. Outcome was measured as standardised mean difference between end-of-trial and baseline scores of negative symptoms.

Results

There were 23 trials from 22 publications (n = 819). The antidepressants involved were selective serotonin reuptake inhibitors, mirtazapine, reboxetine, mianserin, trazodone and ritanserin; trials on other antidepressants were not available. The overall standardised mean difference was moderate (–0.48) in favour of antidepressants and subgroup analysis revealed significant responses for fluoxetine, trazodone and ritanserin.

Conclusions

Antidepressants along with antipsychotics are more effective in treating the negative symptoms of schizophrenia than antipsychotics alone.

Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis

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

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?

Миртазапин в качестве корректора акатизии вызванной антипсихотиками

OBJECTIVE: To evaluate the role of mirtazapine in the treatment of antipsychotic-induced akathisia. DATA SOURCES: MEDLINE (1966-February 2008) and PsycINFO (1967-February 2008) were searched using the terms akathisia and mirtazapine. A bibliographic search was conducted as well. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the search were evaluated. All primary literature was included in the review. DATA SYNTHESIS: Antipsychotic-induced akathisia can be difficult to manage and may respond to mirtazapine based on its antagonist activity at the serotonin 5-HT(2A)/5-HT(2C) receptors. Three case reports (N = 9 pts.), 1 placebo-controlled trial (N = 26), and 1 placebo- and propranolol-controlled study (N = 90) that evaluated mirtazapine for antipsychotic-induced akathisia have been published. Mirtazapine demonstrated a response rate of 53.8% compared with a 7.7% response rate for placebo, based on at least a 2-point reduction on the Barnes Akathisia Scale (global subscale; p = 0.004). Using the same criterion, mirtazapine and propranolol demonstrated efficacy based on response rates of 43.3% and 30.0% compared with placebo (6.7%; p = 0.0051). Mirtazapine was better tolerated than propranolol. In both studies, drowsiness was the most common adverse event associated with mirtazapine. CONCLUSIONS: Mirtazapine may be considered a treatment option for antipsychotic-induced akathisia. It may be especially useful for patients with contraindications or intolerability to beta-blockers and for those with comorbid depression or negative symptoms. Additional studies should be conducted to provide further evidence of mirtazapine's effectiveness in treating akathisia.

pubmed

Резистентные к лечению депрессии

Antidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.
For example, in a study by Thase and colleagues,10 58 patients failed a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not.
Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.
In a study by Zarate and colleagues,21 the onset of the antidepressant effect of ketamine occurred within 2 hours. Unfortunately, the drug must be given by intravenous infusion, but because the effect persisted for 7 days, ketamine treatment may be useful if given as a series.
Another NMDA-receptor antagonist now available in the United States is memantine (FDA-approved for Alzheimer disease). Memantine was shown to be effective in an open-label study in major depression. In a double-blind, randomized trial it showed comparable effects to escitalopram in patients with major depression and alcohol dependence.
Randomized controlled trials have supported the superior efficacy of a TCA/SSRI combination, as well as a mirtazapine/SSRI combination; open studies have done the same for TCA/MAOI and SSRI/bupropion combinations.
As with lithium, a recent review concluded that the trial data that support the efficacy of T3 augmentation are of better quality with TCAs than with SSRIs

Treatment-Resistant Depression

коррекция побочных эффектов психотропных средств

...And then one interesting approach, which may be a little counterintuitive, is to add a small amount of mirtazapine (Remeron). The reason for this is that mirtazapine, which works by stimulating the 5-HT1 receptor and blocking presynaptic autoreceptors, actually blocks two of the serotonin receptors that we think are involved in a lot of serotonergic side effects: 5-HT2 and 5-HT3.
Managing Side Effects of Psychotropics