Tips and pearls

Using micro-titration techniques may improve patient compliance and confidence in the prescriber and the drug prescribed

Most approved antidepressants have an approved starting dose where it has been shown to outperform placebo

Often, clinicians choose to start an off-label, lower dose knowing that it will probably not be therapeutic at all, but the lower dose will likely not have many side effects

As such, patients will be more willing to escalate the dose later after initial success at lower dose and improved initial tolerability

This also dynamically conveys that the prescriber is kind, worried about adverse effects, and wants to minimize suffering

Micro-titrating takes this one step further

• – For example, in this case the patient was started on half of a 25 mg tablet, or 12.5 mg/d of sertraline

• – The usual starting dose is 50 mg/d

• – Sertraline actually comes in a liquid 20 mg/ml concentration

• – Using a 1 cc syringe, a clinician could actually dose this at 2 mg/d initially, if desired, to make a point of really starting at the lowest dose available – a micro-dose (0.1 cc)

• – Literally, her dose could be eye-dropper increased every few days to reach a therapeutic dose

Pharmacokinetic moment

What psychotropic drugs should you know about that inhibit CYP450 2D6?

This patient had a genetic abnormality that rendered her poor and inefficient in processing drugs that require CYP450 2D6 enzyme activity

Sometimes, psychopharmacologists prescribe drugs that iatrogenically create 2D6 deficiencies by inhibiting CYP450 with the same net result as this patient’s genetic deficiencies, i.e., drug intolerability

• – Fluoxetine and paroxetine inhibit CYP450 2D6 maximally

• – Bupropion, duloxetine, haloperidol, perphenazine, thioridazine inhibit CYP450 2D6 moderately

• – Fluvoxamine, sertraline, citalopram, venlafaxine inhibit CYP450 2D6 weakly

Note: Inhibition means that other drugs (substrates) that require 2D6 for metabolism will therefore increase in blood plasma concentrations, likely increasing toxicity side effects.

What drugs should you know that require CYP450 2D6 to be properly metabolized (called substrates)?

Patients who are deficient in CYP450 2D6 or who are inhibited iatrogenically may require lower dosing than normal

Most TCAs are 2D6 substrates and require lower doses

• – In fact, desipramine is often used in testing newly approved drugs to see if they are 2D6 inhibitors

• – If a new drug, when combined with desipramine, elevates desipramine levels, the new drug is considered a 2D6 inhibitor

• – Dextromethorphan, a cough suppressant, may also be used in similar fashion

  • Interestingly, dextromethorphan may have antidepressant qualities when used in neurologically based affective disorders (pseudobulbar affect)

  • Mechanistically, it may dampen glutamate activity to improve crying spells

  • Pharmacokinetically, it is combined in one pill with quinidine

    • Quinidine inhibits CYP450 2D6 allowing for longer sustained plasma levels of the dextromethorphan

    • Here, a drug–drug interaction is used to create a slow-release mechanism for the therapeutic dextromethorphan

    • This combination product is called Nuedexta

The following also may require dose-lowering strategies

• – Bupropion, duloxetine, paroxetine, trazodone, venlafaxine

• – Amphetamine products

• – Atomoxetine

• – Fluphenazine, perphenazine, thioridazine

• – Aripiprazole, risperidone, iloperidone, vortioxetine

What drug–drug interaction combinations are most likely to be seen in psychopharmacological practice?

Notice that some of the previously listed products are both substrates and inhibitors

• – In this way, giving a monotherapy of one of these agents causes 2D6 inhibition, which also increases blood levels of the same drug

• – This is often accounted for when drug dosing is studied through regulatory processes

• – This may explain why certain 2D6-deficient patients might be exquisitely sensitive to even low-dose monotherapy approaches

One of the most common and dangerous 2D6 interactions in practice often involves psychiatric care when there is overlap with primary care

• – This may occur when the psychiatrist is treating depression and the PCP is treating neuropathic pain

• – For example, the psychiatrist may prescribe paroxetine or fluoxetine (SSRIs), both of which are major 2D6 inhibitors

• – The primary clinician may simultaneously prescribe anitriptyline (TCA) for pain or insomnia at seemingly low doses to treat these symptoms off-label

• – However, the SSRI prescribed is likely tripling the plasma level of the TCA in this case

  • If the amitriptyline is 10 mg/d this might be acceptable, but if the TCA is dosed at 50 mg/d, it may be equivalent now to 150 mg/d

  • In this case, especially in those older than 50 years, an EKG and blood levels should be obtained and monitored

  • The likelihood of serotonin syndrome increases as both the TCA and the SSRI are at full doses and both markedly inhibit the SERT

• – Another similar interaction occurs when primary care utilizes the muscle relaxant cyclobenzaprine (Flexeril), as this drug is essentially a TCA

• – Carbamazepine (Equetro) is also a TCA-structured drug

A common combination strategy for resistant depression includes the mixture of bupropion and an SSRI

• – As noted, bupropion may inhibit its own degradation, thus elevating its own levels

• – It has been shown to be safe at doses of 400–450 mg/d depending on the preparation used

• – Clearly doses higher than this elevate risks of seizure activity

• – If maximally dosed, bupropion is combined with an SSRI with known 2D6 inhibition, bupropion levels will elevate up to concentrations above safety levels, thus increasing seizure risk

• – Again, fluoxetine/paroxetine use will raise bupropion levels the most, citalopram moderately, sertraline and escitalopram the least

• – One should consider antidepressants that involve the least inhibition interference with 2D6 when combining with bupropion, such as desvenlafaxine or mirtazapine

Finally, over-the-counter cough suppressants that contain dextromethorphan can also have their levels tripled by major 2D6 inhibitors

• – Similar to the TCA drug–drug CYP450 2D6 interactions discussed earlier, levels may increase that ultimately produce QTc prolongation and possible ventricular arrhythmias

Posttest self-assessment question and answer

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)

Answer: B

Desipramine is a TCA that has very easy-to-determine blood levels and may be tracked effortlessly in clinical trials. When an experimental new drug is going through federal regulatory processes, it is often tested in combination with desipramine to determine if this TCA’s level will increase above the norm, thus signaling a CYP450 2D6 inhibition interaction by the experimental drug. The other three agents undergo hepatic glucuronidation and do not require CYP450 isoenzyme involvement, and would not be good tests for CYP450 interactions as such.

References

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Patient file

The Case:

The angry twins

The Question:

Is pharmacologic treatment of personality traits effective?

The Dilemma:

There are no approved medications for personality disordered patients

Pretest self-assessment question (answer at the end of the case)

Which of the following are approved for treating mood swings?

A. Fluoxetine (Prozac)

B. Lamotrigine (Lamictal)

C. Asenapine (Saphris)

D. Alprazolam (Xanax)

E. All of the above

F. None of the above