Pretest self-assessment question (answer at the end of the case)
Which of the following medications is often used in regulatory trials to determine if a CYP450 inhibition interaction exists with an experimental drug?
A. Temazepam (Restoril)
B. Desipramine (Norpramin)
C. Desvenlafaxine (Pristiq)
D. Paliperidone (Invega)
Patient evaluation on intake
Psychiatric history
The patient had been psychiatrically healthy until she was treated with interferon
While on treatment she developed marked insomnia initially, which was then followed by more fulminant depression and anxiety symptoms
Now experiencing full MDD symptoms
– Except that she denies suicidal thoughts but has ideational guilt that she is a bad spouse and mother and that she has let her family down by being incapacitated and unable to do much of anything around the home
– Experiencing marked agitation and restlessness routinely during the day and has insomnia at night
– Is very tired, fatigued, unfocused, and unmotivated
Does meet criteria for GAD prior to the onset of this MDE
– Worries excessively
– Is tense, keyed up, on edge
– Has insomnia
– Additionally admits to panic or agitation attacks that are sustained for hours
She did not experience these when euthymic, or prior to her interferon treatment
There is no evidence of psychosis, mania, substance misuse
Spouse and family are supportive
She has traveled to specific inpatient depression treatment programs for advice and brings her extensive workup to her initial session
Social and personal history
Graduated from college with a bachelor’s degree
Married and has a grown daughter
A school teacher by trade, but has been unable to teach
Does not misuse alcohol, caffeine, nicotine, or other drugs
Medical history
Chronic severe head, neck, and shoulder pain, which is now exacerbated by MDD
A report showing she is CYP450 hepatic enzyme deficient is reviewed
– 2D6 is markedly deficient (a poor metabolizer)
– 2C19 is moderately deficient
Did not complete interferon treatment for hepatitis C, but is considered stable hepatically nonetheless
Family history
Denies any known psychiatric disorder in any family member
Medication history
Psychotherapy history
No previous experience with psychotherapy and has relied only on PCPs for outpatient pharmacotherapy and inpatient psychiatrists as well
Somewhat receptive to the idea of attending psychotherapy as a treatment option
Patient evaluation on initial visit
Acute onset of MDD symptoms with marked agitation and insomnia roughly six months ago
She seems to be suffering immensely with guilt over her incapacity
– This does not appear to be delusional at this time
She has been noncompliant with medication management thus far as she has developed side effects even to small doses of antidepressants and has declined psychotherapy as an option
She has apparent insight into her acute illness and wants to get better
She has current distrust of medications, and given her workup for liver metabolism enzymes, is convinced that she will get side effects on all medications
Current medications
Question
Should interferon-induced depression respond to antidepressant monotherapy?
Yes
No
Attending physician’s mental notes: initial evaluation
This patient has her first MDE now
This seems superimposed upon GAD, which was likely pre-existing
She is remarkably agitated and looks horribly withdrawn and fatigued
It is acute and precipitated by a medication (Interferon) known to induce MDD in patients being treated for hepatitis
There is some evidence that SSRI and TCA treat interferon-induced depression
Her initial failure to a subtherapeutic SSRI and SNRI is possibly alarming, but her issue has been intolerance, not inefficacy
She was recently started on a minimally therapeutic dose of a third antidepressant in a novel class
– Mirtazapine (Remeron) is an NaSSA antidepressant
– It is unlikely to be problematic
She has known CYP450 2D6 and 2C19 genetic enzyme deficiencies
Mirtazapine pharmacokinetics include
Approximately 100% of the orally administered dose is excreted via urine and feces within four days
Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes
Inhibitors of these isoenzymes (or those with genetic enzyme deficiencies) cause modest increases in mirtazapine plasma concentrations (17% and 32%, respectively) usually without leading to clinically relevant consequences as mirtazapine has multiple routes of metabolism and clearance
Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of co-administered drugs are usually unaffected
However, her documented CYP450 2D6 liver enzyme deficiency will predispose her to side effects of many drugs and many psychotropics will need to be dose-modified during her care
– Her first two reactions (to an SSRI and SNRI) and side effects clearly worsened her agitation and her trust of psychotropics
– She seems convinced and determined that she will be hurt by all interventions
Her clear isoenzyme deficiencies, anxiety, and hypochondriacal thought processes make her prognosis difficult to determine
Question
Which of the following would be your next step?
Increase the mirtazapine (Remeron) to the full FDA dose of 45 mg/d
Increase the alprazolam (Xanax) to a higher, more effective dose to treat her agitation
Change to a more effective hypnotic agent to better treat her insomnia
Review her current medications further to see if any are CYP450 2D6 or 2C19 substrates that are likely to be poorly metabolized and induce immense side effects
Continue to motivationally suggest she consider psychotherapy as a side-effect-free treatment
Attending physician’s mental notes: initial evaluation (continued)
This patient seems to be undertreated due to
– Clear medical reasons (CYP450 2D6 and 2C19 deficiencies)
– Phobic reactions given her initial experience with interferon and her antidepressants
– Good doses/duration of antidepressant treatment have not been utilized
– Much rapport/trust building and very slow titrations will likely be needed to treat her effectively
All prescribing will need to be cross-checked for CYP450 2D6 and 2C19 interactions as she is vulnerable to toxicity and side effects if agents are metabolized through these isoenzyme systems
It is possible that her liver is more affected by her hepatitis C than we suspect, causing her to process medications even more poorly. Could she be a candidate for sofosbuvir (Sovaldi) as an alternate to interferon treatment?
She seems very guilt-ridden and ruminative about her decline. Will need to continue to investigate if this is delusional
She does meet criteria for MDD
It is unclear if her anxiety is truly comorbid or if her MDD is fostering the anxiety symptoms
If psychosis and comorbid anxiety become more evident, then her prognosis worsens further
Further investigation
Is there anything else you would especially like to know about this patient?
What about details concerning her CYP450 deficiencies? How poor of a metabolizer is she?
Cytochrome CYP450 genotype revealed that she is a poor to intermediate 2D6 metabolizer, and an intermediate 2C19 metabolizer
Therefore, drugs that are metabolized and broken down by these enzymes will not be processed efficiently hepatically, causing increased plasma drug levels and likely greater side effects
In patients like this, each prescribed drug should have its metabolic pathways evaluated before prescribing
Drugs known to interact could be used, but dosing must be adjusted to lower doses to avoid toxicity and side effects
Her current medications may have some interactions
– Zolpidem (Ambien) is largely metabolized through 3A4 enzymes and should not present any interaction as she has no genetic enzyme deficiencies for this isoenzyme
– Alprazolam (Xanax) is metabolized by the 3A4 enzyme system as well
– Mirtazapine (Remeron) 15 mg/d is metabolized, as noted earlier, through 3A4 and 2C19. She should have minimal problems as her mild to moderately deficient 2C19 enzyme system can be adequately supported, again by 3A4 enzymes for which she has no deficiency
What about details regarding her liver functioning in face of her untreated hepatitis C?
This patient has AST and ALT hepatic enzyme levels that fluctuate between 200 U/L and 300 U/L, which are considered three to four times greater than normal values
She is considered to be stable by her gastroenterology physicians, but her liver is at risk for ongoing damage as a result of her hepatitis
Case outcome: first interim follow-up visit four weeks later
Patient was tolerating the low-dose mirtazapine (Remeron) except for carbohydrate-craving side effects
– It was increased to 30 mg/d
Next, she is placed on chromium picolinate 200 mcg/d as an antidote to her carbohydrate cravings
Between sessions insomnia escalates and she calls reporting that she had to take extra zolpidem (Ambien) to compensate
– She panics more when she cannot sleep and her depressive symptoms worsen as a result
– She does not seem to be abusing the hypnotic agent but the pattern is worrisome
Upon return, there is slightly less dysphoria and agitation
Affect is moderately brighter
Carbohydrate craving is moderately diminished
Insomnia is evaluated and appears partially driven by the MDD symptoms, but also has a phobic, fear-like quality more consistent with insomnia as if it were a clear comorbidity in itself
– DSM-5 allows insomnia to be a comorbid diagnosis if it is a focus of clinical attention even if, in part, the insomnia is felt to be secondary to MDD
Admits now to mixing her zolpidem and zolpidem-CR and overusing them as she wakes up in the middle of the night sometimes
Question
What would you do next?
Increase the mirtazapine (Remeron) as she seems to be responding better with each dose escalation
Change her hypnotic agent to another with a longer half-life to allow better sleep maintenance
Change her hypnotic agent from her current, sleep center-selective BZRA zolpidem to a true BZ hypnotic that is less selective and possibly able to allow for hypnosis, anxiolysis, and muscle relaxation
Change her hypnotic to one that is not a controlled substance due to fear of pending addiction
Leave medications the same as she is appearing to respond to moderate-dose mirtazapine
Attending physician’s mental notes: second interim follow-up visit at two months
Despite being a little better, she is not a full responder to full-dose mirtazapine (Remeron)
This drug is involved in the CYP450 system, but its metabolism is divided among different enzymatic pathways
– The patient is not deficient on all pathways and has tolerated this medication well, except for her reported hair loss
– She does not seem to be having any major systemic side effects but is growing wary of the medication
– It is possible that she is having side effects from her CYP450 enzymatic 2C19 deficiency regarding mirtazapine metabolism, but more likely at this point, is highly somatic and suffers anxiety-induced side effects
These are erroneously attributed to the medicine
These are often called “nocebo” effects as they are placebo-induced
She is particularly fixed on the hair loss (approved package insert suggests 1/10,000 chance), refuses augmentation with zinc or selenium, and refuses to accept that it might be related to her stress, that in turn requires more aggressive treatment
She states that she is “fed up” with antidepressants and just needs her sleep and wants to focus on treating her insomnia
She believes that her insomnia drives her MDD symptoms and that her MDD will resolve if she sleeps better
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
