Serotonin receptor antagonism and sleep
The 5-HT2 receptor subfamily is comprised of several types with the three most commonly studied subtypes: 5-HT2A, 5-HT1A, and 5-HT2C
5-HT7 and 5-HT1D receptors have also been evaluated more recently for their hypnotic, circadian, and antidepressant effects
Evidence from both clinical and preclinical studies suggests that 5-HT2A receptors modulate and improve slow wave sleep (SWS) when blocked
– This is considered deep and restorative
– Is often lacking in depressed or fibromyalgia (FM) patients
5-HT2A receptor antagonists may not induce hypnosis, or sleep onset, but once sleep occurs, there is a shift toward more efficient and improved SWS
5-HT2A receptor blockade may promote better sleep by a complex mechanism
– Serotonin typically diminishes cortical glutamatergic arousing neurons by agonizing 5-HT1A receptors and enhances glutamatergic excitatory arousal by stimulation of 5-HT2A receptors
– In effect, antagonizing the 5-HT2A receptor dampens cortical activity to promote some somnolence and fatigue
– This may help maintain deeper sleep throughout the night as normal sleep cycle arousal is lowered (See Figure 11.2)
– Currently there are several compounds (volinanserin, esmirtazapine, pruvanserin, pimavanserin, APD125, AVE8488, HY-10275, ITI-722) in clinical development for the treatment of insomnia that utilize this 5-HT2A receptor antagonism, at least in part, as their hypnotic mechanism of action
Figure 11.2. Mechanisms involved in the sleep/wake cycle.
In the image on the left, glutamate’s excitatory influence arouses the cortex and promotes wakefulness, even at night. On the right, 5-HT2A receptor blockade is noted and glutamate activity lowers, and secondarily, cortical activity is dampened, resulting in deeper, more efficient sleep with less nocturnal awakenings
What about 5-ht1d receptor antagonism?
This autoreceptor may be stimulated by use of triptans to treat migraine headaches
However, as a presynaptic autoreceptor, it may be antagonized by some antipsychotics and result in:
– Facilitated serotonin release
– Facilitated NET as a postsynaptic heteroreceptor
– Facilitated glutamate transmission as a heteroreceptor
– Rodent preclinical models suggest this mechanism may allow for antidepressant activity
– It is unclear if 5-HT1D promotes better sleep
– Combination 5-HT1D antagonist–SSRI antidepressants are being researched; vortioxetine is approved and an antidepressant now
What about 5-ht7 receptor antagonism?
This case discusses some of the complex pharmacodynamics of quetiapine (Seroquel), but other atypical antipsychotics also have unique pharmacodynamic profiles that may contribute to their theoretical potential
5-HT7 receptor antagonism is not a property highly possessed by quetiapine (Seroquel), but is a potential novel mechanism by which other antipsychotics may allow for antidepressant and improved sleep effects
The atypical antipsychotics asenapine (Saphris) and lurasidone (Latuda) possess a higher affinity for this receptor blockade, as does the classic atypical antipsychotic clozapine (Clozaril)
The 5-HT7 receptor seems to be sensitive to light and circadian rhythms and may exert antidepressant potential through this complex mechanism
Perhaps by improving sleep at night, energy and concentration during the daytime (depressive symptoms) may improve
For example, rodent models show antidepressant properties when this receptor is blocked pharmacologically or removed genetically
However, many of these effects will only occur at certain times of the day or the night
It is also worth noting that the SSRI antidepressants boost synaptic serotonin levels, which ultimately causes the downregulation of these 5-HT7 receptors, and which is roughly equivalent to the blockade provided by the atypical antipsychotics noted earlier
– The antidepressant vortioxetine has high affinity for 5-HT7 receptor antagonism
– The atypical antipsychotic with high 5-HT7 receptor antagonism and approval to treat bipolar depression as a monotherapy is lurasidone (Latuda)
Posttest self-assessment question and answer
Which of the following properties of certain atypical antipsychotics lend to their ability to promote and maintain sleep?
A. Histamine-1 receptor antagonism
B. Serotonin-2A receptor antagonism
C. Serotonin-7 receptor antagonis
D. A and B
E. All of the above
Answer: E
The antihistamine property is common to the approved hypnotic doxepin (Silenor) and the over-the-counter sleep aid diphenhydramine (Benadryl), and is shared by some of the atypical antipsychotics. This property helps to initiate sleep while 5-HT2A receptor antagonism of the atypical antipsychotics tends to maintain and promote deeper sleep. 5-HT7 receptor antagonism appears to help circadian rhythms in order to promote appropriate timing and length of sleep duration.
References
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Patient file
The Case:
The man who could not sell anymore
The Question:
What to do when comorbid depression and social anxiety are resistant to treatment
The Dilemma:
Rational subsequent polypharmacy trials may fail to achieve remission
Pretest self-assessment question (answer at the end of the case)
Why might certain atypical antipsychotics interact detrimentally with MAOI antidepressants?
A. Some atypical antipsychotics possess serotonin reuptake inhibitor (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