The Neurobiology of Treatment-Resistant Depression

The Neurobiology of Treatment-Resistant Depression

Treatment-resistant unipolar major depression appears to be the rule rather than the exception. This view is supported by data from the STAR*D program, a multilevel treatment trial for major depression.1 Level 1 treatment was citalopram flexibly dosed from 20 to 60 mg/d (mean dose, 41.8 mg/d) for 12 weeks.1 Even though patients were naive to antidepressant treatment at study entry, only about one third achieved remission, a rate much lower than expected.

Subsequent levels tested alternative treatment methods, including switching to another mono-therapy or combination strategies. Monotherapy options at level 2 included sertraline, venlafaxine, bupropion, or cognitive therapy; combinations included citalopram with bupropion, buspirone, or cognitive therapy. At level 3, patients were treated with nortriptyline, mirtazapine, or augmentation with triiodothyronine or lithium. Level 4 treatments included tranylcypromine or venlafaxine plus mirtazapine.

Progressively higher proportions of patients remitted; remission was ultimately achieved in about two thirds of patients.2 However, a high proportion of patients eventually relapsed during a 1-year follow-up, representing another kind of treatment resistance. Thus, depression proved to be a difficult-to-treat condition even with multiple treatment options.

These data are enlightening in several ways.

  • First, it is clear that some people who do not experience remission via actions in 1 chemical system (eg, serotonin) may do so when another system is activated (eg, norepinephrine).
  • Second, others seem to require effects on 2 or more systems in order to maximize response. This is consistent with the common practice of adding bupropion to an SSRI.
  • Third, treatment resistance is a complex condition in which a treatment may achieve a good initial effect that is lost over time.

Hence, the neurobiology of treatment resistance is likely to involve multiple systems that vary among individuals.

Pharmacokinetic causes of treatment resistance

The definition of treatment resistance hinges on the adequacy of both dosage and duration of treatment. To determine that a person has true treatment-resistant depression, a medication should be dosed through its therapeutic range until 1 of 3 outcomes occurs: (1) sustained remission; (2) a dose-limiting adverse effect (leading to a need to switch to an alternative medication); or (3) the maximum recommended dose is reached. Even meeting these criteria, resistance may occur for pure pharmacokinetic reasons.

Polymorphic variants of CYP

Polymorphic variants of the genes for cytochrome P-450 (CYP) enzymes can yield widely varying plasma levels. The simplest of these effects are polymorphisms that lead to reduced activity of an enzyme such as CYP2D6 or CYP3A4. This can be associated with a much higher than expected plasma level of a given antidepressant drug, leading to unexplained sensitivity to adverse effects of 1 or more medications.3 This, in turn, may explain apparent treatment resistance that is related to adverse effects.

Alternatively, some people are rapid or ultrarapid metabolizers via CYP enzymes. This is a result of a polymorphic variant of a CYP enzyme that yields increased activity or, in the case of CYP2D6, actual duplication of the alleles coding for this protein.4

Currently, there is an AmpliChip test available for both CYP2D6 and 2C19, both of which are involved in the metabolism of multiple antidepressant medications. (Information on the AmpliChip test is available at; accessed July 5, 2007.)

The multidrug-resistance gene

Another factor that may influence the effects of psychotropic drugs is p-glycoprotein (P-gp), also known as the multidrug-resistance gene ABCB1. This protein is present in the GI tract, hepatocytes, and endothelial cells forming the blood-brain barrier.5 The function of P-gp is to extrude xenobiotics (including many drugs) from cells, thereby limiting toxicity.5


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