Case outcome: second interim follow-up visit at two months

Mirtazapine (Remeron) dose is maximized to 45 mg/d

Now taken off all zolpidem preparations and instructed against using sleeping pills in an as-needed measure as these may be a prelude to addiction and misuse

Is given eszopiclone (Lunesta) 2 mg at bedtime as it has a longer half-life for better sleep maintenance, and it is less selective for the BZ1 subreceptor and may have more anxiolytic effects

• – Her pill count and potential for overuse will be closely monitored

• – This hypnotic is metabolized via CYP3A4 and CYP2E1 enzymes and she should not develop marked side effects

This approach maximizes her antidepressant while trying to treat her insomnia and agitation better

The patient calls between sessions to state she is having marked hair loss since the mirtazapine was increased, has mild fatigue, and she wishes to consider stopping it

There is no change in insomnia

There is mild sustained improvement in affective range and activity level

She is felt to be 10%–20% better at most but is hyper-focused on insomnia and side effects

Question

What would you do next?

As she is a minimal responder, remove mirtazapine and try another antidepressant that does not utilize CYP450 2D6 or 2C19 metabolism

As she is a minimal responder and is on a somewhat tolerated antidepressant agent that has less impact, try to convince patient to stay on the mirtazapine and consider an augmentation/combination approach

As patient has 2D6 genetic liver enzyme deficiencies, is somewhat phobic of medications, is preoccupied with insomnia, next prioritize treatment of the insomnia and return to treating the depression once this chief complaint symptom is resolved

Consider TMS or ECT, as these device-based treatments require no CYP450 system metabolism

Consider a nutraceutical such as l-methlyfolate (Deplin) at 15 mg/d or S-adenosyl methionine (SAMe) at 400–800 mg twice daily, as they may be useful adjuntive antidepressant agents and may have minimal if any side effects

• – This patient might be accepting and less side-effect prone by understanding that these complementary alternative medicine (CAM) treatments are “not real prescription antidepressants”

• – They may be considered less risky, more holistic, and her comfort level with medication management may increase

Attending physician’s mental notes: second interim follow-up visit at two months (continued)

This patient has “put her foot down” regarding not using formal antidepressants

Increasing her sedative–hypnotic dose or changing to one with faster absorption, longer half-life, or affinity for the GABA-A receptor is unlikely to remit her depression, but building rapport with the patient may improve her anxiety about medications

If her sleep is improved and her symptoms do lessen, she may be more amenable to antidepressant treatment later

Case outcome: interim follow-up visits at three months

The patient declines antidepressants but agrees to a trial of a bona fide BZ sedative–hypnotic (temazepam [Restoril])

• – As-needed use is not allowed, informed consent and pill counts are strict, and her spouse is now involved in dispensing

• – All BZRA products are discontinued

• – She has been taken off mirtazapine

• – Begins temazepam 7.5 mg at bedtime

• – This drug is chosen as it does not require extensive hepatic enzyme metabolism and is considered one of the safer sedatives to use in liver-impaired patients

  • It is glucuronidized in the liver and does not require p450 enzyme activity

  • It is excreted extensively in the urine

• – Lorazepam (Ativan) and oxazepam (Serax) are similar but approved for anxiolysis, not hypnosis

No change in status, patient did not sleep well on temazepam and felt sedated the next day

• – Insists on stopping it and be returned to the zolpidem-CR (Ambien-CR) as she felt it was the best balance between efficacy and tolerability

Depression, agitation, and insomnia continue

Enters into a discussion regarding possibly restarting an antidepressant but wants absolute proof that one chosen will not bother her CYP450 issues

• – Bibliotherapy using The Black Book of Psychotropic Dosing and Monitoring, 10th edition, or The Top 100 Drug Interactions: A Guide to Patient Management is resourced [perhaps the Epocrates Interaction Check can be used electronically]

• – It is shown to, and reviewed with, the patient present, as are internet resources and her records showing her p450 enzyme deficiencies

• – This seems to improve her affect and lower her apprehension, as p450 medications that would likely render her toxic with side effects are dismissed and safer ones that she can metabolize easily are discussed as treatment possibilities

• – She is given choices that fit her needs

Many antidepressants are reviewed and sertraline (Zoloft) is seen as a low-affinity substrate for CYP450 isoenzymes with CYP2B6 contributing the greatest extent of metabolism, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6

Similar to mirtazapine use in this patient; she is satisfied to try this drug as it is clearly metabolized through many enzymatic pathways for which she is not deficient

Sertraline (Zoloft) also comes in small tablet (25 mg) and liquid preparations so that her dose may be started at extremely low levels