Mechanism of action moment

Why might some antipsychotics interact with MAOI and create serotonin syndrome despite not being officially contraindicated?

All atypical antipsychotics are 5-HT2A receptor antagonists and some are 5-HT2C antagonists

Some atypical antipsychotics carry more MAOI interaction possibilities

• – Ziprasidone (Geodon) has functional SNRI pharmacodynamics

• – SNRIs are fully contraindicated in MAOI use due to serotonin syndrome potential

Ziprasidone (Geodon), aripiprazole (Abilify), brexpiprazole (Rexult), asenapine (Saphris), lurasidone (Latuda), and the active metabolite of quetiapine (Seroquel), norquetiapine, have functional 5-HT1A agonism properties

• – This pharmacodynamic property is utilized by the anxiolytic buspirone (BuSpar) and is also contraindicated in MAOI use

• – However, antipsychotic agents like this may be combined with MAOI by experienced clinicians, using much caution, in very treatment-resistant cases, as some of the serotonin drug interaction properties are weak or sometimes theoretical

  • Risks and benefits need to be weighed on a case-by-case basis in these situations, not unlike when advanced clinicians therapeutically combine MAOI and TCA in TRD patients

Clinically, knowing which atypical antipsychotics carry greater serotonergic activity also predicts those that may theoretically interact negatively with MAOI and should likely be avoided in combination

Two-minute tutorial

5-HT1A receptor agonism in treating depression

How does 5-HT1A receptor agonism help treat depression or anxiety? This mechanism seems important in that

• – Buspirone (BuSpar) antidepressant augmentation is an evidence-based treatment

• – As noted here, many atypical antipsychotics employ this mechanism and are MDD augmentation strategies

• – Two of the latest antidepressants approved, vilazodone (Viibryd) and vortioxetine (Brintellix), utilize this mechanism

SSRIs act indirectly by increasing synaptic levels of serotonin (5-HT)

If 5-HT is depleted, there is no 5-HT release and SSRIs are ineffective

This has been postulated to be the explanation for the lack of SSRI therapeutic actions or loss of therapeutic action of SSRI in some patients

Shown here is how buspirone may augment the action of SSRIs both by repleting serotonin (5-HT) and directly desensitizing 5-HT1A receptors

One theoretical mechanism of how 5-HT is allowed to reaccumulate in the 5-HT-depleted neuron is the shutdown of neuronal impulse flow

If 5-HT release is essentially turned off for a while so that the neuron retains all the 5-HT it synthesizes; this may allow repletion of 5-HT stores

A 5-HT partial agonist such as buspirone, or certain antidepressants or atypical antipsychotics, act directly on somatodendritic autoreceptors to inhibit neuronal impulse flow, possibly allowing repletion of 5-HT stores

Additionally, these agents might boost actions directly at 5-HT1A receptors to help the small amount of 5-HT available in this scenario accomplish the targeted desensitization of 5-HT1A somatodendritic autoreceptors that is necessary for antidepressant actions

Shown here is how buspirone or other 5-HT1A agonists potentiate ineffective SSRI action at 5-HT1A somatodendritic autoreceptors, resulting in the desired disinhibition of the 5-HT neuron

This combination of 5-HT1A agonists plus SSRIs may be more effective, not only in depression but also in other disorders treated by SSRIs, such as OCD and PD

Figure 12.1. Mechanism of action of buspirone augmentation.

Figure 12.2. Mechanism of action of buspirone augmentation.

Figure 12.3. Mechanism of action of buspirone augmentation.

Posttest self-assessment question and answer

Why might certain atypical antipsychotics interact detrimentally with MAOI antidepressants?

A. Some atypical antipsychotics possess SRI properties

B. Some atypical antipsychotics possess SNRI properties

C. Some atypical antipsychotics are partial agonists at 5-HT1A receptors

D. Some atypical antipsychotics are partial agonists at D3 receptors

E. A, B, and C

F. All of the above

Answer: E

As discussed in this chapter, some atypical antipsychotics utilize SSRI, SNRI, and partial 5-HT1A receptor agonism, which may contribute to their antidepressant potential but certainly may lead to hypertensive crisis or serotonin syndrome when combined with an MAOI. D3 receptor agonism is unlikely to affect MAOI use and is a mechanism solely possessed by aripiprazole (Abilify).

References

1.Nandagopal JJ, DelBello MP. Selegiline transdermal system: a novel treatment option for major depressive disorder. Expert Opin Pharmacother 2009; 10:1665–73.

2.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

3.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

4.Schwartz TL, Nihalani N. Tiagabine in anxiety disorders. Expert Opin Pharmacother 2006; 7:1977–87.

5.Schwartz TL, Stahl SM. Optimizing antidepressant management of depression: current status and future perspectives. In: Cryan JF, Leonard BE, eds. Depression: From Psychopathology to Pharmacotherapy. Basel: Karger, 2010; pp. 254–67.

6.Schwartz TL, Petersen T, eds. Depression: Treatment Strategies and Management, 2nd edn. New York, NY: Informa, 2009.

7.Keller D. MAO inhibitors. Cleve Clin J Med 2011; 78:81.

Patient file

The Case:

The woman who thought she was ill, then was ill

The Question:

What to do when medication is not absorbed, nor effective

The Dilemma:

Treating anxiety and agitation in the severely medically ill

Pretest self-assessment question (answer at the end of the case)

What are some usual benefits of slow-release preparation medications?

A. Lower blood plasma levels often allow for less severe adverse effects

B. Extended half-life often allows for once-daily dosing and improved adherence

C. Cost is usually lowered as once-daily dosing is less costly to manufacture

D. Improved effectiveness over the parent immediate-release preparation

E. A and B

F. A, B, and C

G. All of the above