Module 3 Use of antipsychotics for unipolar depression

Flavio Guzmn, MD

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.

Use of antipsychotics in depression

Psychotic depression
MDD not responding to antidepressants

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.

Use in Depression with Psychotic Features

Psychotic depression Clinical features

Delusions Hallucinations

Guilt, Worthlessness

Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

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.

Antipsychotics for Treatment Resistant Depression

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, 6170.

Combination and augmentation

Combination:
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

Biological treatments for TRD

Mood stabilizers
Lithium Anticonvulsants

Antipsychotic agents

Dopamine agonists

Thyroid hormone

Neuromodulation Folic acid Stimulants

ECT rTMS VNS

Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

SGAs used as adjunctive treatment

AD

AD+AP

Olanzapine

Quetiapine

Aripiprazole
Depression not responding to AD

Risperidone

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):980-91.

SGAs as augmentation for MDD

Olanzapine

Aripiprazole

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

Efficacy Acute

SGAs as augmentation for MDD

Olanzapine Quetiapine

Aripiprazole

Risperidone

Efficacy is established for acute treatment, not maintenance treatment.

Efficacy Acute

Not yet determined Maintenance

Nelson, C (2012). Unipolar depression in adults: Treatment with second-generation antipsychotics. In: Peter P Roy-Byrne (Ed.), UpToDate.

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.

SGAs approved as adjunctive treatment for depressive episodes

FDA approved:
Aripiprazole Olanzapine in combination with fluoxetine (OFC) Quetiapine

Theories on the MOA of Antipsychotics for Depression

5-HT2AR inhibits DA and NE release

5-HT2A 5-HT2A

GABA
5-HT2A 5-HT2A

DA
DA

GABA

NE
NE

5-HT2A antagonism promotes DA and NE release

5-HT2A 5-HT2A

GABA
5-HT2A 5-HT2A

DA
DA

GABA

NE
NE

5HT2A antagonism promotes monoamines release in the PFC

Prefrontal cortex Dopamine Norepinephrine Norepinephrine Dopamine VTA-PFC

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.

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.

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 secondgeneration 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