1. Module 3 Use of antipsychotics for unipolar depression
This section is about the use of antipsychotics for unipolar depression.
Flavio Guzmán, MD

2. Outline Use of antipsychotics in:
Antipsychotics: Depressive episodes with psychotic features
Augmentation therapy: major depressive episode
Theories on the mechanism of action of SGAs as antidepressants.
This is the outline for this section:
First I’ll describe the use of antipsychotics in depressive episodes with psychotic features and as augmentation therapy in major depressive disorder.
After that, I’ll review the theories on the mechanism of action of SGAs as antidepressants.

3. Use of antipsychotics in depression
Psychotic depression
MDD not responding to antidepressants
The role of antipsychotics in depression has been established for two clinical situations:
Psychotic depression
Major depressive disorder not responding to antidepressants.

4. Use of antipsychotics in depression
AD+AP AD
AD+AP
Psychotic features
In this slide we can see the two clinical situations in which depression can benefit from antipsychotic treatment.
On the left the figure shows a depressive episode with psychotic features, the red spot points the start of pharmacotherapy. In psychotic depression the antipsychotic is started concurrently with the antidepressant.
The right figure depicts a depressive episode that doesn’t respond sufficiently to antidepressant therapy. In this case, as you can see in the purple spot, the antipsychotic is added after the antidepressant, as adjunctive therapy.
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
Let’s explore a bit more about the use of antipsychotics in depression with psychotic features.

6. Psychotic depression – Clinical features
Guilt, Worthlessness
Delusions
Hallucinations
What are the clinical features of psychotic depression?
First of all, this a severe type of depression. In addition to depressive symptoms, psychotic symptoms such as delusions and hallucinations are frequently consistent with depressive themes of guilt and worthlessness.
Delusions are false and fixed beliefs and hallucinations are most commonly auditory.
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
Often times treatment with antidepressant monotherapy is not enough for improving symptoms in psychotic depression. Patients who have major depression with psychotic features have greater morbidity and mortality than patients with nonpsychotic major depression
Second generation antipsychotics possibly benefit psychotic depression by improving anxiety, agitation and insomnia.
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
We’ll now discuss the use of 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”
There are several definitions for treatment-resistant depression. I chose to include the Ananth 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”
Two successive courses of monotherapy with pharmacological different antidepressants refers to the sequential use of antidepressants of different classes. For example, sertraline and clomipramine. In order to consider a depressive episode resistant, the dose should be the highest therapeutic dose and the time of treatment should be between 8 to 12 weeks.
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
Combination and augmentation are strategies commonly used in the treatment of treatment-resistant depression.
What do we mean when we say combination? Combination is the addition of another medication without expecting potentiation of efficacy of the second drug. Both benefits and side effects are additive.
Augmentation is the use of a drug that might not be effective by itself as an antidepressant, but may enhance the response to a given antidepressant.
In the next slide we’ll see examples of drugs used as augmentation therapy.
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
Here are listed some of the biological treatments used as augmentation for treatment-resistant depression.
Mood stabilizers: this includes lithium and anticonvulsants. Lithium prescriptions declined in the last few years but it’s a useful option for augmentation.
Antipsychotic agents will be discussed in more detail in the next slide
Dopamine agonists
Thyroid hormone
Folic Acid
Stimulants
Nueromodulation, which includes electroconvulsive therapy, repeated transcranial magnetic stimulation and vagus nerve stimulation
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
A recent meta-analysis of second generation antipsychotics vs placebo has shown efficacy of these drugs as adjunctive treatment major depressive disorder. However, the authors point out that the rate of discontinuation due to adverse events was significantly higher for antipsychotics than the placebo group.
There is evidence of efficacy for four second generation antipsychotics: olanzapine, quetiapine, aripiprazole and risperidone.
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.
Olanzapine, quetiapine, aripiprazole and risperidone are similarly efficacious for short term augmentation. Much of the therapeutic benefit occurs within the first two weeks of 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.

14. SGAs as augmentation for MDD
Olanzapine
Quetiapine
Aripiprazole
Risperidone
Efficacy is established for acute treatment, not maintenance treatment.
Efficacy is established for acute treatment but not for maintenance treatment. This poses an important question: for how long should the antipsychotic be prescribed? To date, no studies seem to have addressed this question.
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)
Some of the most commons side effects detected in clinical trials include:
Olanzapine: weight gain and sedation
Quetiapine: dry mouth and sedation
Aripiprazole: akathisia
Risperidone: sedation and dry mouth, but both rates were low.
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
Three second generation antipsychotics are approved as adjunctive treatment of depressive episodes: aripiprazole, olanzapine in combination with fluoxetine, and quetiapine.

17. Theories on the MOA of Antipsychotics for Depression
In this section I review the current theories on how second generation antipsychotics improve depressive symptoms.
As we saw in the mechanisms of action section, most of these antipsychotics are 5HT2A antagonists, we’ll see what is the relationship between 5HT2A antagonism and antidepressant effects.

18. 5-HT2AR inhibits DA and NE release
GABA DA DA
5-HT2A
5-HT2A
Let’s focus our attention on the dopaminergic and noradrenergic neurons depicted here. The release of dopamine and norepinephrine from terminals is influenced by 5-HT2A receptors in the somatodendritic region.
Stimulation of 5-HT2A receptors by serotonin inhibits dopamine and norepinephrine release. This is a direct mechanism.
Also, GABAergic neurons have influence on dopaminergic and noradrenergic neurons. Normally, they release GABA, which inhibits dopamine and norepinephrine release.
Stimulation of 5-HT2A receptors in GABAergic neurons promotes GABA release, which in turn inhibits dopamine and noradrenergic release. This is an indirect mechanism.
GABA NE NE

19. 5-HT2A antagonism promotes DA and NE release
GABA DA DA
5-HT2A
5-HT2A
Here we can see the effects of antagonism on 5HT2A receptors. Blockade of 5HT2A receptors reduces inhibition both in dopamine and norepinephrine release.
Also, if we pay attention to the GABAergic neurons we can see that 5HT2A antagonism inhibits release of GABA. Lower concentrations of GABA in the somatodendritic region disinhibit dopaminergic and noradrenergic neurons, promoting dopamine and norepinephrine release.
GABA NE NE

20. 5HT2A antagonism promotes monoamines release in the PFC
Prefrontal cortex
Dopamine
VTA-PFC
Dopamine
Norepinephrine
Norepinephrine
The conclusion is that 5HT2A antagonism promotes release of monoamines in the prefrontal cortex.
Here in red we can see dopamine projections from the ventral tegmental area to the prefrontal cortex.
In blue, noradrenergic projections from the locus ceruleus to the prefrontal cortex.
To sum up, antagonism of 5-HT2A receptors by second generation antipsychotics increases release of dopamine and norepinephrine in the prefrontal cortex.
5HT2C antagonism has also been proposed as a possible mechanism of antidepressant actions, some antipsychotics such as olanzapine are 5HT2C antagonists.
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.
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