____________________________________________________________________________ Anxiety Disorders
Milnacipran Milnacipran (Savella) has been marketed in France since 1997 for the treatment of major depression, but it is indicated for use by the FDA solely for fibromyalgia [178]. Milnacipran is not available in a generic formulation, and the expiration of the patent is not imminent. Anxiolytic effects of milnacipran are at least partially mediated by 5-HT2A receptor agonism [188; 195]. Results of a systematic review were inconclusive regard- ing the comparative efficacy, acceptability, and tolerability of milnacipran versus other antidepressive agents; however, mil- nacipran reportedly was more favorable than TCAs in terms of acceptability and tolerability [196]. Levomilnacipran Levomilnacipran (Fetzima) differs from other SNRIs in that it is a more potent and selective inhibitor of norepinephrine than serotonin, especially at low doses. Alcohol may disrupt the extended-release mechanism to release large amounts of drug over a brief period, and co-ingestion should be avoided. With reports of milnacipran increasing hepatic transaminases to cause fulminant hepatitis, levomilnacipran should be avoided in patients with a history of alcoholism or chronic liver disease. Levomilnacipran is not associated with weight gain [173; 178]. Levomilnacipran ER 40–120 mg daily was found to be effective in preventing relapse in patients with major depressive disorder [197].
Mirtazapine Mirtazapine (Remeron) is a tetracyclic compound with a unique mechanism of action, leading to description as a noradrenergic antagonist-specific serotonin antagonist antide- pressant. Pharmacologically, mirtazapine is a 5-HT1 receptor agonist, and antagonism of 5-HT2A/C receptors increases cortical serotonin, dopamine, and norepinephrine modula- tion. Inhibition of norepinephrine alpha-2 autoreceptors allows greater norepinephrine release from neuron terminals. Also antagonized are receptors of 5-HT3, 5-HT5, and H1 his- tamine. This unique profile helps account for earlier onset of action than SSRI/SNRIs. Mirtazapine tends to promote sleep or drowsiness, and the most frequent side effect of daytime sedation can be a beneficial effect in highly anxious patients [178; 179; 188]. Mirtazapine is found beneficial in patients with GAD, SAD, OCD, panic disorder, and PTSD [200]. It is relatively safe in overdose. Mirtazapine is particularly useful in patients with sexual dysfunction from other antidepressants and is a good choice in patients with significant insomnia. Weight gain is a side effect, and if the risks for elevated lipid levels and rare agranulocytosis are a concern, mirtazapine may be reserved as a third-line choice [200; 201]. Agomelatine Agomelatine is approved for clinical use in Europe, Australia, and a total of 40 countries overall, but not by the FDA. It is discussed in light of its novel mechanism and particular benefit in GAD [202]. Agomelatine is a synthetic melatonin analog with activity as a melatonin MT1/MT2 receptor agonist and 5-HT2C receptor antagonist. Unique to agomelatine, and one of its most impor- tant properties, is a sleep-promoting and pro-chronobiologic effect. Its 5-HT2C antagonism promotes dopaminergic firing in the ventral tegmental area, frontal cortex, hypothalamus, hippocampus, medulla, pons, and retina by enhancing norepi- nephrinergic activity in the locus coeruleus [185; 203]. With a unique non-monoaminergic mechanism of action, clinical trials have shown a low risk of sexual dysfunction, lack of weight gain or withdrawal symptoms, and overall side effect profile similar to placebo. However, reports of liver injury require patients to receive liver enzyme monitoring [204].
Other Antidepressants Bupropion
Bupropion (Wellbutrin) lacks effect on serotonin neurotrans- mission either presynaptically (through serotonin release or reuptake inhibition) or postsynaptically (acting on serotonin receptors). Instead, bupropion inhibits the reuptake of norepinephrine and dopamine without affecting release or transport of other neurotransmitters and without binding to other neurotransmitter receptors. This unique pharmacologic profile makes bupropion the only approved antidepressant that increases dopamine neurotransmission in the nucleus accumbens and prefrontal cortex. The side effect profile, distinct from other antidepressants, lacks sexual dysfunction, weight gain, and sedation. The activating effects of bupropion can increase insomnia and anxiety, leading to its infrequent use in anxiety disorders [179; 198]. Trazodone and Nefazodone The anxiolytic effects of trazodone are mediated by activity as a highly potent 5-HT2A receptor antagonist and moderately potent 5-HT1A partial agonist, with additional activity in SERT and 5-HT2C receptor inhibition. The combined actions of 5HT2A/5HT2C antagonism and SERT inhibition only occur at moderate-to-high doses, with doses lower than effec- tive for antidepressant action frequently used for the effective treatment of insomnia [178; 179; 199]. Nefazodone (Serzone) is highly similar in pharmacologic activity to trazodone, but it is rarely prescribed due to liver toxicity concerns [179].
Anti-Epileptic Drugs Gabapentinoids
Pregabalin (Lyrica) and gabapentin (Neurontin) are structurally analogous GABA analogs, with pregabalin more extensively evaluated in anxiety disorders. The anxiolytic, antinociceptive, and antiseizure properties of pregabalin are mediated through binding to presynaptic α 2 δ subunits of central nervous system (CNS) voltage-gated calcium channels, which decreases calcium influx at presynaptic channels and inhibits neurotransmis- sion of excitatory glutamate, norepinephrine, and substance P [185; 205].
109
EliteLearning.com/Psychology
Powered by FlippingBook