Treating Major Depression: Antidepressant Algorithms

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and Pittsburgh Medical Center, Philadelphia and Pittsburgh

The treatment of depression has progressed such that clinicians currently have a large number of pharmaceutical options available for use. Because of the multiple antidepressant options, clinicians are encouraged to employ treatment algorithms, the fundamental rationale being that treatment algorithms enable care providers to pick the most appropriate pharmacotherapy for a particular patient at a given time.1 Essentially, algorithms are organizers that help sequence the use of specific medications or treatment strategies. Treatment algorithms generally include a hierarchy of medications starting with those that are most widely used as first-line agents and moving through alternate first-line options and/or augmentation strategies, more widely used second-line options, and so on. A patient usually starts with a medication from the first group in the hierarchy and then if, because of either intolerance or nonresponse, 1 of those first-line medications is not sufficient, moves to the next step of the sequence (AV 1AV 1).2

SSRIs as Standard First-Line Antidepressants

As of early 2009, the first line of antidepressant treatment for depression is typically an SSRI. The popularity of SSRIs is due in part to an improved safety profile compared with older antidepressants, particularly the TCAs. The SSRIs are better tolerated, have less risk of lethal overdose, and have fewer cardiovascular side effects than TCAs. For clinicians, SSRIs are easy to prescribe because, unlike with the TCAs, they generally do not need to be started at one third or one quarter of the target dose and then up-titrated to minimize side effects and facilitate tolerability. Patients treated with SSRIs can usually be started at a full therapeutic dose and, because SSRIs are safer in overdose, a full 30-day supply may be prescribed. Patients treated with TCAs typically require more frequent follow-up because as few as a 7-day supply taken at once can be fatal. Thus, the SSRIs offer safety, convenience, and better tolerability than many other antidepressants and, for the most widely treated groups of patients—depressed outpatients—the SSRIs are at least as effective as the TCAs.

The SSRIs have held first-line treatment status for almost 20 years because none of the drugs that have subsequently been introduced have offered a compelling reason to replace them. Each of the newer non-SSRIs may have a few advantages over the SSRI class, but none has a substantial enough advantage to supplant the SSRIs. Because 5 SSRIs are approved for use in the United States for the treatment of depression, many clinicians opt to go through at least 2 or 3 SSRI treatment trials before they leave the class.

While SSRIs are significantly better tolerated than TCAs, they are not without side effects. A common and distressing side effect of SSRI treatment is sexual dysfunction. Many patients who take SSRIs report some unwelcome change in their sex lives. Delayed orgasm is the most common sexual dysfunction associated with this class of medication, the most severe presentation of which is anorgasmia.

Other limitations of the SSRI class include a lack of uniform effect across some key symptom domains associated with depression, including insomnia and anxiety. For instance, patients who have high levels of anxiety associated with their depression have a lower likelihood of response to treatment, despite the fact that SSRIs are indicated for the treatment of anxiety disorders such as generalized anxiety disorder, social anxiety disorder, panic disorder, and post-traumatic stress disorder. The development of alternate medications or augmentation strategies that effectively target anxiety and other depressive symptom domains is an important topic for future research.

SSRI Alternatives in Depression Treatment Algorithms

The most widely used alternatives to SSRI antidepressant therapy include the SNRIs venlafaxine and duloxetine; bupropion, a nonserotonergic antidepressant that works primarily through norepinephrine and possibly dopamine mechanisms; mirtazapine, a tetracyclic compound that does not inhibit reuptake but rather affects norepinephrine and serotonin through alternate mechanisms; and TCAs, which are primarily noradrenergically acting medications.

Because the SNRIs affect norepinephrine as well as serotonin, they have the potential for greater efficacy or a broader range of therapeutic effects, although the involvement of the second monoamine pathway also increases the possibility of medication-related adverse events. In fact, concerns regarding side effects and a lack of multiple inexpensive generic SNRI formulations are the primary reasons that the dual reuptake inhibitors have not supplanted SSRIs as the first-line treatment class in many treatment algorithms. Many of the SSRIs are available in generic formulations, but currently the only member of the SNRI class that is available as a generic is the immediate-release form of venlafaxine.

Bupropion does not have direct serotonergic effects and therefore has essentially no risk of treatment-emergent sexual dysfunction,3,4 so it provides a useful alternative for patients who have experienced unacceptable sexual side effects with the SSRIs or the SNRIs. Mirtazapine is structurally similar to TCAs and, like some of the tertiary amine tricyclics, is relatively sedating and has the largest risk of weight gain of any of the newer antidepressants. Yet, for patients who have tolerability problems with SSRIs, mirtazapine is sometimes an excellent choice. So, in algorithms, SSRIs are typically the first choice, SNRIs or bupropion second, and then, based on individual patient concerns, mirtazapine or TCAs come third or fourth.


A Need for Improved Antidepressant Pharmacotherapies

Despite the variety of available antidepressants, no antidepressant has strong efficacy. In clinical trials, only about half of the patients respond to first-line antidepressant medications.5 Sometimes, almost as many patients who take placebo reach the same level of improvement as those who take an active antidepressant, which indicates a relatively modest efficacy advantage for antidepressant medications.6 Additionally, all current antidepressants are relatively slow in exerting therapeutic effects and usually do not reliably lift mood for 2 weeks or more. Generally, responders do not reach a sufficient level of improvement until about the fourth week of treatment. Because remission is the targeted outcome, 6 or 8 weeks may be required in order to determine the effectiveness of an antidepressant medication.5

For patients who do not respond sufficiently to first-line treatment, therapeutic decrement becomes an issue. Each time a patient moves to a new step in a treatment algorithm, the odds of that patient achieving remission decrease. In fact, more than 40% of patients may have unresolved depressive symptoms after 4 treatment attempts (AV 2AV 2).7 Clinicians have the best chance of getting patients into remission with the first treatment trial, so matching the first-line selection in a treatment algorithm to the individual patient’s needs must be considered carefully. New antidepressants with the tolerability and safety of SSRIs but with improved efficacy would be useful additions to the pharmacotherapeutic antidepressant arsenal.

Drug Names

bupropion (Aplenzin, Wellbutrin, and others), buspirone (Buspar and others), citalopram (Celexa and others), duloxetine (Cymbalta), lithium (Eskalith, Lithobid, and others), mirtazapine (Remeron and others), nortriptyline (Pamelor and others), sertraline (Zoloft and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others)


HAM-D-17=17-item Hamilton Rating Scale for Depression
SNRI=serotonin-norepinephrine reuptake inhibitor
SSRI=selective serotonin reuptake inhibitor
STAR*D=Sequenced Treatment Alternatives to Relieve Depression
TCA=tricyclic antidepressant

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