Antidepressants: Is a higher dose always better?

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor