Selective Serotonin–Norepinephrine Reuptake Inhibitors

For a more detailed discussion of this topic, see Selective Serotonin-Norepinephrine Reuptake Inhibitors, Sec. 31.26, p. 3184, in Comprehensive Textbook of Psychiatry, 9th Edition.

There are currently three serotonin–norepinephrine reuptake inhibitors (SNRIs) approved for use in the United States: venlafaxine (Effexor and Effexor XR), desvenlafaxine succinate (DVS; Pristiq), and duloxetine (Cymbalta). A fourth SNRI, milnacipran (Savella), available in other countries as an antidepressant, has Food and Drug Administration (FDA) approval in the United States as a treatment for fibromyalgia. The term SNRI reflects the belief that the therapeutic effects of these medications are mediated by concomitant blockade of neuronal serotonin (5-HT) and norepinephrine uptake transporters. The SNRIs are also sometimes referred to as dual reuptake inhibitors, a broader functional class of antidepressant medications that includes tricyclic antidepressants (TCAs) such as clomipramine and, to a lesser extent, imipramine and amitriptyline. What distinguishes the SNRIs from TCAs is their relative lack of affinity for other receptors, especially muscarinic, histaminergic, and the families of α- and β-adrenergic receptors. This distinction is an important one because the SNRIs have a more favorable tolerability profile than the older dual reuptake inhibitors.

Venlafaxine and Desvenlafaxine

Therapeutic Indications

Venlafaxine is approved for treatment of four therapeutic disorders: major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder. Major depressive disorder is currently the only FDA-approved indication for DVS.

Depression

The FDA does not recognize any class of antidepressant as being more effective than any other. This does not mean that differences do not exist, but no study to date has sufficiently demonstrated such superiority. It has been argued that direct modulation of serotonin and norepinephrine may convey greater antidepressant effects than are exerted by medications that selectively enhance only noradrenergic or serotoninergic neurotransmission. This greater therapeutic benefits could result from an acceleration of postsynaptic adaptation to increased neuronal signaling; simultaneous activation of two pathways for intracellular signal transduction; additive effects on the activity of relevant genes such as brain-derived neurotrophic factor; or, quite simply, broader coverage of depressive symptoms. Clinical evidence supporting this hypothesis first emerged in a pair of studies conducted by the Danish University Antidepressant Group, which found an advantage for the dual reuptake inhibitor clomipramine compared with the selective serotonin reuptake inhibitors (SSRIs) citalopram and paroxetine. A third report, which compared the results of a group
of patients prospectively treated with the combination of the TCAs desipramine and fluoxetine with a historical comparison group treated with desipramine alone, provided additional support. A meta-analysis of 25 inpatient studies comparing the efficacy of TCAs and SSRIs yielded the strongest evidence. Specifically, although the TCAs were found to have a modest overall advantage, superiority versus SSRIs was almost entirely explained by the studies that used the TCAs that are considered to be dual reuptake inhibitors—clomipramine, amitriptyline, and imipramine. Metanalyses of head-to-head studies suggest that venlafaxine has a potential to induce higher rates of remission in depressed patients than do the SSRIs. This difference of the venlafaxine advantage is about 6%. DVS has not been extensively compared with other classes of antidepressants with respect to efficacy.

Generalized Anxiety Disorder

The extended-release formulation of venlafaxine is approved for treatment of generalized anxiety disorder. In clinical trials lasting 6 months, dosages of 75 to 225 mg a day were effective against insomnia, poor concentration, restlessness, irritability, and excessive muscle tension related to generalized anxiety disorder.

Social Anxiety Disorder

The extended-release formulation of venlafaxine is approved for treatment of social anxiety disorder. Its efficacy was established in 12-week studies.

Other Indications

Case reports and uncontrolled studies have indicated that venlafaxine may be beneficial in the treatment of obsessive-compulsive disorder, panic disorder, agoraphobia, social phobia, attention-deficit/hyperactivity disorder, and patients with a dual diagnosis of depression and cocaine dependence. It has also been used in chronic pain syndromes with good effect.

Precautions and Adverse Reactions

Venlafaxine has a safety and tolerability profile similar that of the more widely prescribed SSRI class. Nausea is the most frequently reported treatment-emergent adverse effect associated with venlafaxine and DVS therapy. Initiating therapy at lower dosages may also attenuate nausea. When extremely problematic, treatment-induced nausea can be controlled by prescribing a selective 5-HT₃ antagonist or mirtazapine.

Venlafaxine and DVS therapy is associated with sexual side effects, predominantly decreased libido and a delay to orgasm or ejaculation. The incidence of these side effects may exceed 30 to 40% when there is direct, detailed assessment of sexual function.

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