Nocturnal Insomnia, Anxiety, and Tremor in an 88‑Year‑Old on Aripiprazole, Doxepin, and Melatonin

The most likely cause is akathisia from aripiprazole 5 mg, and the first step is to discontinue aripiprazole immediately while initiating Cognitive Behavioral Therapy for Insomnia (CBT‑I) and optimizing low‑dose doxepin to 6 mg at bedtime.

Primary Culprit: Aripiprazole‑Induced Akathisia

Aripiprazole commonly causes akathisia—an inner sense of restlessness with motor agitation—which manifests as nocturnal anxiety, tremor, and inability to remain still in bed. 1
The FDA label for aripiprazole explicitly lists akathisia, restlessness, tremor, anxiety, and insomnia as frequent adverse effects, occurring in a substantial proportion of patients. 1
In elderly patients, aripiprazole carries heightened risks of falls, cognitive impairment, and movement disorders; the American Academy of Sleep Medicine issues a strong recommendation against using antipsychotics for primary insomnia due to weak efficacy evidence and significant harms. 2
Discontinue aripiprazole immediately and reassess symptoms within 1–2 weeks; akathisia typically resolves within days to weeks after stopping the offending agent. 21

Secondary Contributors

Subtherapeutic Doxepin Dosing

Doxepin 6 mg is the recommended dose for sleep‑maintenance insomnia in older adults, but this patient is receiving only 6 mg; the American Academy of Sleep Medicine recommends starting at 3 mg and titrating to 6 mg if sleep‑maintenance problems persist. 23
Low‑dose doxepin (3–6 mg) reduces wake after sleep onset by 22–23 minutes, has minimal anticholinergic effects at hypnotic doses, and carries no abuse potential. 23
Increase doxepin to 6 mg at bedtime (if not already at that dose) and reassess after 1–2 weeks for improvement in nocturnal awakenings. 23

Melatonin 10 mg: Excessive Dose

Melatonin 10 mg exceeds guideline‑recommended doses (0.5–1.5 mg) and yields only a modest ~9‑minute reduction in sleep latency, providing minimal benefit for primary insomnia. 4
The American Academy of Sleep Medicine recommends against melatonin supplements for chronic insomnia due to insufficient evidence of efficacy and poor FDA regulation of product quality. 2
Discontinue melatonin 10 mg; if circadian support is needed, consider ramelteon 8 mg (a melatonin‑receptor agonist with FDA approval) after optimizing behavioral therapy. 24

Mildly Elevated TSH (5.18)

Subclinical hypothyroidism (TSH 5.18) can contribute to insomnia, anxiety, and tremor through increased sympathetic activation and metabolic dysregulation. 5
Optimize thyroid replacement to normalize TSH (target 0.5–2.5 mIU/L in older adults) and reassess symptoms after 6–8 weeks of stable dosing. 5

Low Total CO₂ (16 mEq/L)

A total CO₂ of 16 mEq/L indicates metabolic acidosis, which can cause anxiety, tremor, and sleep disruption through respiratory compensation and sympathetic activation. (General medical knowledge)
Evaluate for underlying causes (e.g., renal insufficiency, diabetic ketoacidosis, lactic acidosis, chronic diarrhea) and correct the acidosis; symptoms often improve once the acid‑base disturbance is resolved. (General medical knowledge)

First‑Line Behavioral Therapy (Mandatory Before Adding Medication)

The American Academy of Sleep Medicine and the American College of Physicians issue a strong recommendation that all adults with chronic insomnia receive Cognitive Behavioral Therapy for Insomnia (CBT‑I) as the initial treatment before any pharmacotherapy. 23
CBT‑I provides superior long‑term efficacy with sustained benefits after discontinuation, whereas medication effects cease when stopped. 23
Core CBT‑I components include:
- Stimulus control: Use the bedroom only for sleep; leave the bed if unable to fall asleep within ~20 minutes; return only when sleepy; maintain consistent sleep‑wake times; avoid daytime napping. 23
- Sleep restriction: Limit time in bed to match actual sleep time (calculated from a 1–2‑week sleep diary), maintaining sleep efficiency ≥85 %; adjust weekly by 15–20 minutes based on sleep efficiency. 23
- Sleep hygiene: Cool, dark, quiet bedroom; avoid evening caffeine, nicotine, alcohol; avoid vigorous exercise within 2 hours of bedtime; limit fluids before sleep. 23
- Relaxation techniques: Progressive muscle relaxation, guided imagery, or diaphragmatic breathing at bedtime. 23
CBT‑I can be delivered via individual therapy, group sessions, telephone, web‑based modules, or self‑help books, all of which demonstrate comparable efficacy. 23

Pharmacologic Algorithm (After Aripiprazole Discontinuation and CBT‑I Initiation)

Step 1: Optimize Low‑Dose Doxepin

Increase doxepin to 6 mg at bedtime (if not already at that dose) and reassess after 1–2 weeks for improvement in sleep‑maintenance insomnia. 23
If doxepin 6 mg is ineffective after 2 weeks, switch to an alternative agent rather than adding a second hypnotic. 2

Step 2: Alternative Pharmacologic Options (If Doxepin Fails)

Suvorexant 10 mg (orexin‑receptor antagonist) reduces wake after sleep onset by 16–28 minutes and carries a lower risk of cognitive and psychomotor impairment than benzodiazepine‑type agents. 2
Ramelteon 8 mg (melatonin‑receptor agonist) has no abuse potential, is not DEA‑scheduled, and does not cause withdrawal; appropriate for patients with a history of substance use. 2
Eszopiclone 1–2 mg (start at 1 mg in elderly) improves both sleep onset and maintenance, increasing total sleep time by 28–57 minutes; FDA labeling limits use to ≤4 weeks for acute insomnia. 23

Step 3: Medications to Avoid

Benzodiazepines (e.g., temazepam, lorazepam, clonazepam) are contraindicated in older adults due to higher risk of falls, cognitive impairment, dependence, and dementia. 23
Over‑the‑counter antihistamines (e.g., diphenhydramine, hydroxyzine) have anticholinergic effects that can accelerate cognitive decline and cause daytime hypersomnolence; they should be avoided. 23
Trazodone yields only ~10 minutes reduction in sleep latency and ~8 minutes reduction in wake after sleep onset, with no improvement in subjective sleep quality; the American Academy of Sleep Medicine recommends against its use for primary insomnia. 2
Antipsychotics (e.g., quetiapine, olanzapine) have weak evidence for insomnia benefit and significant risks (weight gain, metabolic dysregulation, extrapyramidal symptoms, increased mortality in elderly with dementia). 2

Safety Monitoring and Reassessment

Reassess symptoms after 1–2 weeks of aripiprazole discontinuation to confirm resolution of akathisia, anxiety, and tremor. 21
Monitor sleep‑onset latency, total sleep time, nocturnal awakenings, and daytime functioning at every visit. 23
Screen for complex sleep behaviors (e.g., sleep‑driving, sleep‑walking, sleep‑eating) at every visit; discontinue any hypnotic immediately if such behaviors occur. 2
Evaluate for comorbid sleep disorders (e.g., obstructive sleep apnea, restless‑legs syndrome, REM‑behavior disorder) if insomnia persists beyond 7–10 days despite appropriate treatment. 23
Recheck TSH and total CO₂ after 6–8 weeks of thyroid optimization and acidosis correction; symptoms often improve once metabolic disturbances are resolved. 5

Common Pitfalls to Avoid

Do not add a second hypnotic (e.g., benzodiazepine or Z‑drug) to doxepin; this creates dangerous polypharmacy with additive CNS depression, respiratory risk, falls, and cognitive impairment. 2
Do not continue aripiprazole for "sleep" when it is causing akathisia; antipsychotics are contraindicated for primary insomnia. 21
Do not initiate pharmacotherapy without concurrent CBT‑I, as behavioral therapy yields more durable improvements than medication alone. 23
Do not use adult dosing in older adults; age‑adjusted dosing (e.g., eszopiclone ≤2 mg, zolpidem ≤5 mg) is essential to reduce fall risk. 23
Do not overlook medication‑induced insomnia; aripiprazole, SSRIs, β‑blockers, and diuretics are common culprits in older patients. 31

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