Dangerous Atypical Antipsychotics Minimally Effective for Depression

You may be familiar with the television commercials for aripiprazole (ABILIFY). Featuring such characters as a moody umbrella[1] and an amorphous blob diligently transcribing a doctor's orders,[2] the ads tout aripiprazole as a remedy for major depression. Aripiprazole is classified as an atypical antipsychotic — a class of drugs usually used to treat serious mental illnesses, such as schizophrenia and bipolar disorder. It also is one of three drugs in that class (the others are quetiapine extended-release [SEROQUEL XR] and the combination drug olanzapine-fluoxetine [SYMBYAX]) that are approved to treat major depression in patients without another serious mental illness.[3]

However, the ads do not mention that aripiprazole, like the other two atypical antipsychotics mentioned above, was not very effective in improving depressive symptoms in clinical trials. In addition, all three drugs come with serious side effects that make it advisable to explore other, safer options before resorting to a potent antipsychotic medication for major depression.

However, the ads do not mention that aripiprazole, like the other two atypical antipsychotics mentioned above, was not very effective in improving depressive symptoms in clinical trials. In addition, all three drugs come with serious side effects that make it advisable to explore other, safer options before resorting to a potent antipsychotic medication for major depression.

Slight benefits for major depression

The first of the three atypical antipsychotics approved by the Food and Drug Administration for major depression in patients without other, more serious mental illnesses was aripiprazole, in 2007.[4] Approval for olanzapine-fluoxetine[5] and quetiapine extended-release[6] followed in 2009. Aripiprazole and quetiapine extended-release are approved as add-on therapies to antidepressants, whereas olanzapine-fluoxetine combines an antipsychotic with an antidepressant. All three approvals were based on clinical trials in which the antipsychotics were administered to subjects in whom one or more antidepressants had not been fully effective in improving their major depression.[7],[8],[9]

In each of these three cases, all but one of the major clinical trials used to support approval were too short (under 12 weeks) to draw any conclusions about the drugs' long-term effectiveness in patients with major depression.

And aripiprazole and quetiapine extended-release, when added to an antidepressant, were only slightly better than a placebo in improving short-term symptoms of major depression. Both drugs lowered subjects' scores (indicating fewer symptoms) on a 60-point depression symptom scale by only approximately three extra points over the placebo.[10],[11] While these differences were statistically significant, three-point reductions on a 60-point scale are of questionable real-life importance for patients with major depression. The five trials for the olanzapine-fluoxetine combination were less conclusive, with four of the five failing to show that the combination was clearly better than each drug given separately (the drug was not compared to a placebo).[12]

The relevance of these findings to patients' daily lives was assessed in a 2013 review of all clinical trials of atypical antipsychotics as add-on treatment for major depression.[13] While the review confirmed that all studied antipsychotics resulted in "small to moderate" on depression questionnaires, these improvements did not generally translate into better daily functioning or quality of life for the subjects. The authors concluded that doctors should be cautious in prescribing atypical antipsychotics as add-on therapy for major depression, given their questionable effectiveness as well as what they described as "the abundant evidence of potential treatment-related harm."

Serious side effects

The "abundant evidence" of harm with atypical antipsychotic use is apparent from the drugs' labels. Every atypical antipsychotic carries a black-box warning of an increased risk of death in elderly patients with dementia-related psychosis and states that use in these patients should be avoided.[14] Because the drugs are approved for major depression, aripiprazole, quetiapine extended-release, and olanzapine-fluoxetine also have a black-box warning of an increased risk of suicidal thoughts and behaviors if used in children, adolescents and young adults.

Atypical antipsychotics also are associated with, among other side effects:

• Weight gain.
• Increased blood sugar and Type 2 diabetes.
• Negative effects on blood cholesterol levels.
• Severe and potentially irreversible involuntary movements (known as tardive dyskinesia).
• Impairment of thought and motor skills.
• Dangerously low blood pressure.
• Low white blood cell counts (increasing risk of infection).
• Seizures.
• Cataracts (quetiapine only).
• A potentially fatal condition known as neuroleptic malignant syndrome.

Aripiprazole,[15] quetiapine extended-release,[16] and olanzapine-fluoxetine[17] also exhibit dangerous interactions with dozens of medications. adolescents and young adults.

What You Can Do

Not everyone who is sad has major depression, and not everyone who is depressed is a suitable candidate for antidepressant medication. Psychotherapy always should be the first treatment for depression of any severity, because it is just as effective as antidepressants[18] and has no negative side effects. If psychotherapy is not available or unaffordable, and if you are severely depressed, antidepressants also could help, but you should review the benefits and risks of each medication with your doctor.

The safest antidepressants are known as selective serotonin reuptake inhibitors, or SSRIs (examples include fluoxetine [PROZAC] and sertraline [ZOLOFT]), and should be tried first. However, like all antidepressants, even SSRIs carry a black-box warning of an increased risk of suicide when used in young adults.[19] If you are still severely depressed even after trying an antidepressant, you first should consider, with your doctor, either increasing the dose of that antidepressant, if it is safe to do so, or switching to another antidepressant. You may have to try more than one to find the SSRI that works for you.

We recommend that you add aripiprazole or quetiapine extended-release to your antidepressant only if you are still severely depressed after trying at least two different SSRIs. Because neither drug was studied for long-term use in major depression, you should carefully discuss with your doctor whether the drugs are working and still necessary a few weeks after beginning therapy and periodically thereafter.

We also recommend that you not use the olanzapine-fluoxetine combination, as its effectiveness was not conclusively demonstrated. In addition, a combination medicine does not allow for dose adjustment of each individual drug, which is especially important in determining appropriate treatments for major depression. Use of a combination medicine also can make it difficult to determine which drug is responsible for any side effects that emerge over time.

For more information on depression treatments, see "How Effective Are Antidepressants for Depression?" in the February 2014 issue of Worst Pills, Best Pills News.[20] If you experience suicidal thoughts or urges, call 911 or the National Suicide Prevention Lifeline at 800-273-TALK (8255) immediately, or go to the emergency room.[21]

References

[1] YouTube. Abilify TV commercial. Uploaded May 19, 2014. https://www.youtube.com/watch?v=RHewdmUEMxE. Accessed September 23, 2015.

[2] YouTube. Abilify TV commercial. Uploaded February 27, 2011. https://www.youtube.com/watch?v=tGymr78FtbU. Accessed September 23, 2015.

[3] Food and Drug Administration. FDA-Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed September 17, 2015.

[4] Food and Drug Administration. Letter of approval for aripiprazole for major depression. November 16, 2007. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/021436s018,%20021866s005,%20021729s005,%20021713s013ltr.pdf. Accessed September 22, 2015.

[5] Food and Drug Administration. Approval package for NDA 21-520/S-012 (olanzapine-fluoxetine for treatment-resistant depression). March 19, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021520Orig1s012.pdf. Accessed September 23, 2015.

[6] Food and Drug Administration. Letter of approval for quetiapine extended-release for major depression. December 2, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022047s011s016s017s019s022ltr.pdf. Accessed September 23, 2015.

[7] Food and Drug Administration. Medical review for NDA 21436 (aripiprazole for the adjunctive treatment with antidepressant therapy of major depressive disorder). September 2007. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021436s018_MedR.pdf. Accessed September 22, 2015.

[8] Food and Drug Administration. Approval package for NDA 22-047/S-011 (quetiapine fumarate for adjunctive therapy in the treatment of major depressive disorder). December 2, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022047Orig1s011.pdf. Accessed September 23, 2015.

[9] Food and Drug Administration. Approval package for NDA 21-520/S-012 (olanzapine-fluoxetine for treatment-resistant depression). March 19, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021520Orig1s012.pdf. Accessed September 23, 2015.

[10] Food and Drug Administration. Medical review for NDA 21436 (aripiprazole for the adjunctive treatment with antidepressant therapy of major depressive disorder). September 2007. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021436s018_MedR.pdf. Accessed September 22, 2015.

[11] Food and Drug Administration. Approval package for NDA 22-047/S-011 (quetiapine fumarate for adjunctive therapy in the treatment of major depressive disorder). December 2, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022047Orig1s011.pdf. Accessed September 23, 2015.

[12] Food and Drug Administration. Food and Drug Administration. Approval package for NDA 21-520/S-012 (olanzapine-fluoxetine for treatment-resistant depression). Memorandum by Thomas P. Laughren, director, Division of Psychiatry Products. March 23, 2007. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021520Orig1s012.pdf. Accessed September 23, 2015.

[13] Spielmans GI, Berman MI, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: A meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10(3):e1001403.

[14] National Institutes of Health. DailyMed. http://dailymed.nlm.nih.gov/dailymed/. Accessed September 17, 2015.

[15] Aripiprazole (ABILIFY) drug interactions. Worst Pills, Best Pills News. April 2010. /newsletters/view/687. Accessed September 23, 2015.

[16] Quetiapine (SEROQUEL) interactions with other drugs. Worst Pills, Best Pills News. February 2010. /newsletters/view/678. Accessed September 23, 2015.

[17] National Institutes of Health. DailyMed. Olanzapine-fluoxetine label. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b28c424-0b7e-4b75-b090-f116b113554e. Accessed October 7, 2015.

[18] Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT, Reynolds CF 3rd. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry. 2013;12(2):137-148.

[19] National Institutes of Health. DailyMed. http://dailymed.nlm.nih.gov/dailymed/. Accessed September 17, 2015.

[20] How effective are antidepressants for depression? Worst Pills, Best Pills News. February 2014. /newsletters/view/890. Accessed September 22, 2015.

[21] National Suicide Prevention Lifeline. http://www.suicidepreventionlifeline.org/. Accessed September 23, 2015.