New research shows that while many antidepressants help most people who take them, a small group of people who take them will actually feel more depressed than if they had just been taking a placebo or sugar pill.Some People Feel Worse on Antidepressants Like Cymbalta
Abstract
Purpose of review The aim of this systematic review was to examine the efficacy and safety of second-generation antipsychotics (SGAs) in nonpsychotic major depressive disorder (MDD).
Recent findings In MDD, SGA monotherapy or adjunctive therapy to conventional antidepressants showed rapid onset of antidepressant efficacy. Although maintenance data are limited, quetiapine monotherapy, risperidone adjunctive therapy, and amisulpride adjunctive therapy significantly delayed the time to relapse as compared with placebo. In general, extrapyramidal symptoms appeared to be low with SGAs, but a higher incidence of akathisia was observed with aripiprazole. An elevated risk of weight gain was observed with olanzapine–fluoxetine combination, risperidone, aripiprazole, and quetiapine compared with placebo. At present, there are insufficient data to confidently distinguish between different SGAs in the treatment of MDD. A recent meta-analysis found that adjunctive SGAs were significantly more effective than placebo, but differences in efficacy were not identified among the studied agents, nor were outcomes affected by trial duration or the method of establishing treatment resistance.
Summary Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of MDD than placebo, but augmentation is more widely utilized in treatment-resistant depression. Clinicians should routinely monitor for cardiometabolic side-effects and extrapyramidal symptoms during SGA therapy.
Quetiapine
The efficacy and safety of QTP-XR monotherapy in the treatment of MDD were evaluated in two 8-week, placebo-controlled RCTs.[7••,8•] In the first trial, QTP-XR 150 or 300 mg/day and duloxetine 60 mg/day were compared with placebo.[7••] All active treatment arms demonstrated significant improvement in Montgomery–Asberg Depression Rating Scale (MADRS)[27] total scores compared with that of placebo at week 6. Significant improvement in depressive symptoms occurred at the end of week 1 with both QTP-XR 150 mg/day (−8.4, P < 0.01) and 300 mg/day (−8.2, P < 0.01) compared with placebo (−6.0), but not duloxetine 60 mg/day (−6.8, P = 0.30). At study endpoint (week 6), remission rates (MADRS ≤ 8) were significantly higher in the QTP-XR 300 mg/day (32.0%, P < 0.05) and duloxetine 60 mg/day groups (31.9%, P < 0.05) vs. placebo (20.4%), but not for QTP-XR 150 mg/day (26.5%, P = 0.27).
Sulpiride and Amisulpride
Apart from QTP-XR, SLP and ASLP are the only other SGAs that have been studied as monotherapy treatment for MDD in placebo-controlled trials. A moderately sized (n = 88) study found greater reduction in the 21-item Hamilton Depression Rating Scale (HAM-D-21)[28] total score from baseline to endpoint in the SLP group (−10, P = 0.0007) than in placebo (−8). The only RCT of ASLP in the acute treatment of MDD compared a fixed dosage of ASLP 50 mg/day (n = 136) with paroxetine 20 mg/day (n = 136).[11] No statistically significant differences occurred between the two treatments, but a placebo group was not included to establish internal validity.[11] A long-term (6-month), fixed-dosage, placebo-controlled RCT in mild or moderate MDD or dysthymia compared the efficacy and safety of ASLP (50 mg/day) with imipramine (100 mg/day) and placebo.[12] Analysis of the primary outcome showed the mean change in MADRS total scores in both active treatment arms was significantly larger than that of placebo, although remission rates did not reach the level of statistical significance.
"Ms. L" was a 49-year-old woman with chronic depression and postoperative cellulitis following a bunion excision. She was evaluated on the medical unit. She endorsed depressive symptoms, auditory hallucinations, and suicidal thoughts. The patient had previously attempted suicide twice by drug overdose. Her most recent suicide attempt was 7 months prior. Previous responses to sertraline and citalopram were poor. At the time of assessment on the medical unit, she was receiving duloxetine (40 mg twice daily), aripiprazole (1 mg/day), clonazepam (1 mg twice daily), and amoxicillin/clavulanate (850 mg twice daily).
The patient was started on duloxetine 7 months before. Ten days prior to admission, her primary care physician had started her on aripiprazole (2 mg/day) for augmentation. She denied a history of psychotic symptoms and drug or alcohol abuse as well as a family history of psychosis.
Three days after starting aripiprazole, Ms. L reported auditory hallucinations. She was paranoid regarding her ex-husband. She described command hallucinations from the devil, who meant to harm her, and could also hear God's voice encouraging her not to listen to the devil. She experienced concurrent onset of suicidal ideation with no plan. She was fully oriented, with no evidence of confusion. Aripiprazole was reduced to 1 mg/day, which led to amelioration of her hallucinations. However, her suicidal thoughts and paranoid beliefs persisted.
The psychiatric consultant decided to discontinue aripiprazole, leading to rapid and complete resolution of the patient's psychotic symptoms and suicidal ideation. Her ongoing depression was managed with duloxetine (60 mg twice daily).
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]Adjunctive Use of Atypical Antipsychotics for Treatment-resistant Generalized Anxiety DisorderTable 1. Summary of Clinical Trials of Adjunctive Use of Atypical Antipsychotics for Treatment-Resistant Generalized Anxiety Disordera
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 improvedNR Aripiprazole[33] Open label 23 8 10.5 HAM-A: −6.7
CGI-S: −12.5 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 ill11 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: −1.533.9 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.
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 |
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."
