1. Module 3 Use of antipsychotics for unipolar depression
Flavio Guzmán, MD

2. Outline Use of antipsychotics in:
Depressive episodes with psychotic features
Augmentation therapy: major depressive episode
Theories on the mechanism of action of SGAs as antidepressants.

3. Use of antipsychotics in depression
Psychotic depression
MDD not responding to antidepressants

4. Use of antipsychotics in depression
AD+AP AD
AD+AP
Psychotic features
Psychotic depression
Depression not responding to AD
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

5. Use in Depression with Psychotic Features

6. Psychotic depression – Clinical features
Guilt, Worthlessness
Delusions
Hallucinations
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

7. Therapeutic issues - Psychotic depression
Normally antidepressant monotherapy is not enough.
SGAs possibly benefit psychotic depression by improving anxiety, agitation and insomnia.
AD+AP
Psychotic features
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

8. Antipsychotics for Treatment Resistant Depression

9. Treatment-resistant depression (TRD)
Definition: “Failure to respond adequately to two successive courses of monotherapy with pharmacological different antidepressants given in an adequate dose for sufficient length of time”
Ananth J (1998) Treatment-resistant depression. Psychotherapy and Psychosomatics 67, 61–70.

10. Combination and augmentation
addition of another medication without expecting potentiation of efficacy of the second drug.
Benefits and side effects are additive
Augmentation:
Might not be effective by itself as antidepressant
May enhance response to a given antidepressant
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

11. Biological treatments for TRD
Mood stabilizers
Lithium
Anticonvulsants
Antipsychotic agents
Dopamine agonists
Thyroid hormone
Folic acid
Stimulants
Neuromodulation
ECT
rTMS
VNS
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

12. SGAs used as adjunctive treatment
Olanzapine
Quetiapine
Aripiprazole
Risperidone AD
AD+AP
Depression not responding to AD
Can also be used for psychotic depression
Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):

13. SGAs as augmentation for MDD
Olanzapine
Quetiapine
Aripiprazole
Risperidone
Olanzapine, quetiapine, aripiprazole and risperidone are similarly efficacious for short term augmentation.
Efficacy
Not yet determined
Acute
Maintenance
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

14. SGAs as augmentation for MDD
Olanzapine
Quetiapine
Aripiprazole
Risperidone
Efficacy is established for acute treatment, not maintenance treatment.
Efficacy
Not yet determined
Acute
Maintenance
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

15. Side effects Olanzapine: weight gain and sedation
Quetiapine: dry mouth and sedation
Aripiprazole: akathisia
Risperidone: sedation and dry mouth (low rates)
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

16. SGAs approved as adjunctive treatment for depressive episodes
FDA approved:
Aripiprazole
Olanzapine in combination with fluoxetine (OFC)
Quetiapine

17. Theories on the MOA of Antipsychotics for Depression

18. 5-HT2AR inhibits DA and NE release
GABA DA DA
5-HT2A
5-HT2A
GABA NE NE

19. 5-HT2A antagonism promotes DA and NE release
GABA DA DA
5-HT2A
5-HT2A
GABA NE NE

20. 5HT2A antagonism promotes monoamines release in the PFC
Prefrontal cortex
Dopamine
VTA-PFC
Dopamine
Norepinephrine
Norepinephrine
Locus ceruleus-PFC
Further information:
Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.

21. Key Points Antipsychotics are effective in the treatment of:
Psychotic depression
Treatment resistant depression
Olanzapine, quetiapine and aripiprazole are FDA approved as adjunctive drugs for TRD.
5-HT2A antagonism could explain antidepressant effects of antipsychotic drugs.

22. References and further reading
Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2010.
Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008