Question

What would you do next?

Continue sequentially trying the atypical class of antipsychotics

Return to use of a typical antipsychotic

Continue trying to treat the somatic symptoms with sedatives and/or antidepressants

Case outcome: interim follow-up visits through 24 months

Patient is engaged in a discussion about typical versus atypical antipsychotics

• – He has lost faith in the atypical antipsychotics and views them as having more anxiety and somatic symptom-inducing side effects

• – The last atypical antipsychotic is discontinued and he is titrated onto thiothixene (Navane), a thioxanthene-based high-potency (affinity) typical antipsychotic

• – At 4 mg/d he is no longer “freezing” and the usual negative symptoms continue, but he no longer has somatic anxiety

• – Continues clonazepam (Klonopin) now at 2 mg/d

• – Needs no sleep-inducing medications

Presents later with an unfortunate return of his marked insomnia

Question

What would you do next?

Use an antipsychotic combination by adding quetiapine (Seroquel) back into his regimen as it was successful before

Increase the partially effective BZ clonazepam (Klonopin) further

Add a different BZRA hypnotic agent

Add an antihistamine at night to improve his sleep

Add a melatonergic sleep agent at night

Attending physician’s mental notes: interim follow-up visits through 24 months

For the insomnia, escalating GABAergic drugs failed to help last time

Adding an atypical antipsychotic with strong antihistamine (and other pharmacodynamic) properties was quite effective previously

Do not want to add quetiapine (Seroquel) back as he was developing metabolic problems on it last time, and often antipsychotic polypharmacy is frowned upon clinically

An over-the-counter antihistamine hypnotic could be issued, such as diphenhydramine or doxylamine

A prescription TCA-based antihistamine could be added, such as doxepin (Silenor/Sinequan)

The thiothixene (Navane) is working well; it likely should be augmented with a sleeping pill that is not GABA-based, such as melatonergic ramelteon (Rozerem) or onexin inhibiting suvorexant (Belsomra)

Case outcome: interim follow-up visits through 24 months (continued)

The MT1/MT2 receptor agonist hypnotic (ramelteon [Rozerem]) became available and is prescribed at 8 mg at bedtime, to no avail

• – It was used off-label next at 16 mg at bedtime, without effect, and was discontinued

Doxepin, initially approved as a TCA at doses of 150–300 mg/d, was re-evaluated at lower doses as a non-addictive, H1 receptor antagonist hypnotic agent

• – Therefore, doxepin (Silenor) was prescribed at the usual 6 mg at bedtime dose

The patient was also maintained on his typical antipsychotic and low-dose BZ

Case debrief

The patient suffers from schizophrenia

Generally experiences good psychotic symptom control

He continued with either premorbid ASD symptoms, or schizophrenia-induced negative symptoms throughout

Like many schizophrenics, he developed side effects that needed to be managed

He also developed the comorbidity of insomnia and hypochondriacal thinking that needed to be managed

Typical of an illness that may last decades, sometimes dealing with comorbidities and secondary illnesses is the focus of schizophrenia patient care

He sleeps well now, usually with 6 mg/d of doxepin (Silenor), but has permission to double the dose in an off-label manner for breakthrough insomnia

It is likely in this case that the routine use of his GABAergic BZ anxiolytic caused his BZ and BZRA hypnotics not to be effective due to tachyphalaxis or tolerance. His GABA-A receptors theoretically became insensitive due to similar mechanistic agents being used

Attempts to use a non-GABAergic hypnotic that is melatonin enhancing, e.g., ramelteon (Rozerem), made clinical sense as it has a different mechanism of action, but this failed

Knowledge of quetiapine’s (Seroquel) H1 receptor antagonism and its effectiveness in treating the patient’s insomnia earlier guided the choice to a formal antihistamine hypnotic (Doxepin [Silenor]) in the end, with successful results

• – Theoretically, the TCA doxepin should have much less metabolic syndrome and TD/EPS side effects to contend with compared to the previously used atypical antipsychotic quetiapine