Since the serendipitous discovery of the ► antidepressant effects of tricyclics in the 1950s, depression has generally been treated by agents that boost the synaptic actions of one or more of the three ► monoamines (serotonin (5HT), ► norepinephrine (NE), and ► dopamine (DA)). Acutely enhanced synaptic levels of monoamines could lead to adaptive downregulation and desensitization of postsynaptic receptors over time, a pharmacological action consistent with current ► aminergic hypotheses of depression, which posit that the disorder may be due to the pathological upregulation of neurotransmitter receptors (Stahl 2008a). Thus, antidepressants theoretically reverse this pathological upregulation of receptors over time. Adaptive changes in receptor number or sensitivity are likely the result of alterations in ► gene expression and transcription. This may include not only turning off the synthesis of neurotransmitter receptors but also increasing the synthesis of various ► neurotrophic factors such as ► brain-derived neurotrophic factor (BDNF). In fact, preclinical studies demonstrate that antidepressants increase BDNF expression (Duman et al. 2001). Such prototrophic actions may apply broadly to all effective antidepressants and may provide a final common pathway for the action of antidepressants.
Although treatment with currently available antide-pressants is effective for many patients, a large proportion experience residual symptoms, treatment resistance, and relapse. In the recent STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study (Warden et al. 2007), only one-third of the patients on monotherapy with ► citalopram remitted initially. For those who failed to remit, the likelihood of ► remission with another anti-depressant monotherapy decreased with each successive trial. Thus, after a year of treatment with four sequential antidepressants taken for 12 weeks each, only two-thirds of patients achieved remission (Fig. 1). Of additional concern is the fact that the likelihood of relapse increased with the number of treatments it took to get the patient to remit.
These results highlight the need for the continued exploration of more effective methods to treat major depression. A plethora of treatments are either under investigation or newly available for major depressive disorder, including new formulations of current antidepressants, new and existing agents that exploit the monoaminergic link to depression, and experimental agents with novel mechanisms of action.
One developmental focus for antidepressants is to improve the tolerability of existing agents. A recently approved hydrobromide salt formulation of ► bupropion allows the administration of single-pill doses up to 450 mg equivalency to bupropion hydrochloride salt, unlike bupropion hydrochloride controlled release formulations for which the biggest dose in a single pill is 300 mg. This could facilitate dosing for difficult-to-treat patients.
In addition, approval is pending for a once-daily controlled release formulation of ► trazodone that allows
Antidepressants: Recent Developments. Fig. 1. Remission rates in major depressive disorder with sequential monotherapies.
much more tolerable administration of high antidepressant doses (e.g., 300-450 mg). This may increase the utility of trazodone in depression, as the immediate release formulation is often not tolerated at high antidepressant doses due to its propensity to cause severe next-day sedation, and is used instead at low doses as a hypnotic.
► desvenlafaxine, the active metabolite of ► venlafaxine, as a unique antidepressant agent. Desvenlafaxine is formed as the result of CYP450 2D6 and thus itself bypasses this metabolic step, potentially giving it more consistent plasma levels than venlafaxine (Stahl 2009). In addition, although desvenlafaxine, like venlafaxine, is more potent at the 5HT ► transporter (SERT) than the NE transporter (NET), it has relatively greater actions on NET versus SERT than venlafaxine does at comparable doses. This greater potency for NET may make it a preferable agent for symptoms theoretically associated with NE actions, such as pain symptoms and vasomotor symptoms. In fact, desvenlafaxine was shown to be efficacious for hot flushes in perimenopausal women (Stahl 2008a; Wise et al. 2008), although it was not approved for this use due to cardiovascular safety concerns.
New Means of Monoaminergic Modulation
Atypical Antipsychotic Drugs
Currently, atypical ► antipsychotic drugs are used to treat
► bipolar disorder, with similar efficacy to each other in the manic phase but varying efficacy in treating the depressed phase. Several mechanisms are feasible explanations for how certain atypical antipsychotic drugs may work to improve symptoms in the depressed phase of bipolar disorder (Stahl 2008a). Actions at numerous receptors by different atypical antipsychotic drugs can increase the availability of 5HT, DA, and NE, which, as discussed earlier, are critical in the action of current anti-depressants in unipolar depression (Fig. 2). Specifically, actions at 5HT2A, 5HT2C, and 5HT1A receptors indirectly lead to NE and DA disinhibition, which may improve mood and cognition. Mood may also be improved by increasing NE and 5HT via actions at alpha 2 adrenergic receptors, by increasing NE via the blockade of the NE transporter, and by increasing 5HT via actions at 5HT1D receptors and the blockade of the 5HT transporter. Anti-histamine actions could improve insomnia associated with depression. Actions at other 5HT receptors may also play a role in treating depression.
Each atypical antipsychotic has a unique portfolio of pharmacological actions that may contribute to its anti-depressant actions (Fig. 3). This may explain why these agents differ in their ability to treat the depressed phase of ► bipolar disorder and also why some patients respond to one of these drugs and not to another. The agent with the most evidence of efficacy as a monotherapy for bipolar depression is ► quetiapine, which was recently approved for this indication. The effective dose of quetia-pine in bipolar depression is 300-600 mg/day, lower than
Antidepressants: Recent Developments. Fig. 2. Pharmacologic properties of atypical ► antipsychotic drugs and their links to symptoms of depression.
that needed for the saturation of the D2 receptor but sufficient to cause 5HT2C antagonism, 5HT1A agonism, and norepinephrine reuptake inhibition, especially through the newly discovered pharmacologic actions of its active metabolite norquetiapine (Stahl, 2008a, 2009). This lends further weight to the speculative mechanisms described earlier for antidepressant action of atypical an-tipsychotic drugs.
Whether atypical antipsychotic drugs will be proven effective with a sufficiently favorable side effect and cost profile for unipolar depression is still under intense investigation (Papakostas et al. 2007). ► Aripiprazole was recently approved as an adjunct treatment for resistant depression (defined as failing one SSRI/SNRI trial). At its effective dose in depression - 2-10 mg/day, lower than that used for ► schizophrenia - aripiprazole is
Fig. 3. Atypical antipsychotic drugs: differing portfolios of pharmacologic action for
Antidepressants: Recent Developments.
Fig. 3. Atypical antipsychotic drugs: differing portfolios of pharmacologic action for primarily a D2 and D3 ► partial agonist with only weak 5HT2A ► antagonist and 5HT1A partial agonist properties (Stahl 2008b).
Triple Reuptake Inhibitors (TRIs)
These drugs are testing the idea that if one mechanism is good (i.e., selective serotonin reuptake inhibitors or SSRIs [► SSRIs and related compounds]) and two mechanisms are better (i.e., serotonin and norepinephrine reuptake inhibitors or ► SNRI antidepressants), then maybe targeting all three mechanisms of the trimonoamine neurotransmitter system would be the best in terms of efficacy. Several different triple reuptake inhibitors (or serotonin-norepinephrine-dopamine reuptake inhibitors) are listed in Table 1 (Stahl 2008a). Some of these agents have additional pharmacological properties as well. In particular, LuAA 24530, currently in clinical trials, is not only a TRI but also binds 5HT2C, 5HT2A, 5HT3, and alpha 1A adrenergic receptors. The question regarding TRIs is how much blockade of each monoamine transporter is desired, especially for the dopamine transporter or DAT. Too much dopamine activity can lead to a drug
Triple reuptake inhibitor
Additional receptor targets
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