Tips and pearls

Two SSRI antidepressants are approved for treating PTSD: paroxetine (Paxil) and sertraline (Zoloft)

In recent years, prazosin (Minipress) has acquired an evidence base to support its off-label use in alleviating PTSD nightmares specifically. This would have been a reasonable option in this case

The beta-blockers have some limited evidence that, if utilized quickly after a trauma, they blunt hyperautonomic responses and that the risk for developing full syndromal PTSD may be less. This would have been less helpful in this case as her trauma was not recent

The atypical antipsychotics and antiepileptic medications also have a limited evidence base that supports their use in PTSD

The sedatives are controversial as PTSD patients have high addiction rates

A pharmacodynamic moment

Why do some atypical antipsychotics make good hypnotic agents?

First, using an atypical antipsychotic to treat insomnia has risks and benefits

• – Pros

  • Relatively fast onset

  • Non-addictive

  • May induce sleep onset and improve deep sleep propensity

• – Cons

  • Risk of serious side effects that other hypnotics do not have (TD, EPS, metabolics, cataracts [interestingly, follow-up long-term studies suggest little risk, but FDA language still suggests diligence in monitoring here for quetiapine], QTc prolongation, stroke in certain populations)

Many atypical antipsychotics are antihistamines

• – H1 receptor antagonism causes sedation and somnolence as a result of lowering wakefulness center (tuberomammillary nucleus [TMN]) activity while promoting sleep center (ventrolateral preoptic [VLPO] area) activity

• – This enhances the brain’s sleep–wake switch to favor sleep

• – The faster acting and reliably absorbed atypical antipsychotics, each with a shorter half-life, may be better suited as hypnotic agents as they may have more dependable sleep onset and less morning hangover effect

Some atypical antipsychotics possess serotonin-2A (5-HT2A) receptor antagonism

• – This mechanism appears to help maintain patients in a sleeping state by promoting more efficient and deeper sleep

• – In this way, these antihistamine effects may initiate sleep and 5-HT2A blocking effects may maintain deeper or more efficient sleep

At higher doses, atypical antipsychotics antagonize D2 receptors

• – This mechanism is known to calm agitated patients who are psychotic

• – It is possible this calming effect lowers anxiety and cortical hyperarousal at bedtime, allowing better sleep onset

This profile of H1, 5-HT2A, and D2 antagonism is unique to the atypical antipsychotics and is not found in any approved hypnotic agent

If approved hypnotic agents fail to aid in sleep initiation or maintenance then atypical antipsychotics may be a reasonable choice

Antihistamine and the sleep–wake switch

The hypothalamus is a key control center for sleep and wakefulness, and the specific circuitry that regulates sleep/wake is called the sleep/wake switch

The “off” setting, or sleep promoter, is localized within the VLPO of the hypothalamus, while “on”, wake promoter, is localized within the TMN of the hypothalamus

Two key neurotransmitters regulate the sleep/wake switch: histamine from the TMN and GABA from the VLPO

• – When the TMN is active and histamine is released in the cortex and into the VLPO, the wake promoter is on and the sleep promoter is inhibited (Figure 11.1A)

  • H1 receptor antagonists, antihistamines, block this wakefulness pathway whereby the released histamine transmitter cannot activate frontal lobe neurocircuitry, causing a loss of arousal and resultant fatigue

• – When the VLPO is active and GABA is released into the TMN, the sleep promoter is on and the wake promoter inhibited (Figure 11.1B)

• – The sleep/wake switch is also regulated by orexin/hypocretin neurons in the lateral hypothalamus (LAT), which stabilize wakefulness, and by the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the body’s internal clock and is activated by melatonin, light, and activity to promote either sleep or wakefulness

Figure 11.1. A and B. Sleep/wake switch.