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The structures of these two compounds derive from those of the fluorobutyrophenone antipsychotics. They have ff- arylamine-like structures that permit binding to the SERT and inhibit 5-HT reuptake. In these compounds, the additional hydrophobic substituent can be viewed as being attached to the nitrogen of the ff-arylamine-like group. Additionally, they are 5-HT2A antagonists. That antagonism may or may not afford antipsychotic effectiveness is discussed under antipsychotics. 5-HT2A antagonists appear to have antidepressant and anxiolytic activities. They may act, at least in part, by enhancing 5-HT1A activities.33 Also, some of the effects may be mediated through 5-HT2C agonism

(perhaps generally so for 5-HT-acting antidepressants). Some of the side effects of SSRIs are considered to be mediated through 5-HT2A receptors, so a 5-HT2A blocker would reduce them.33 The two compounds yield the same compound on N-dealkylation. It is a serotonin reuptake inhibitor.

The most common use of trazodone is not as an antidepressant. A 100-mg dose can be used as a sedative-hypnotic. Despite this use, it has been shown that nefazodone produces better sleep hygiene than does trazodone, which is a rapid eye movement (REM)-suppressing compound.

5-HT1A Agonists and Partial Agonists


The initial compound in this series, buspirone (BuSpar), has anxiolytic and antidepressant activities and is a partial 5-HT1A agonist. Its anxiolytic activity is reportedly caused by its ability to diminish 5-HT release (via 5-HT1A agonism). High short-term synaptic levels of 5-HT are characteristic of anxiety. Also, because it is a partial agonist, it can stimulate postsynaptic receptors when 5-HT levels are low in the synapse, as is the case in depression. Several other spirones are in development as anxiolytics and antidepressants.34

a2 Antagonists


Mirtazapine (Remeron) was recently introduced for clinical use in the United States; its parent mianserin (pyridyl N replaced with C-H) was long known to be an antidepressant. It is reported to be faster acting and more potent than certain SSRIs. The mode of action gives increased NE release via a2-NE receptor antagonism and increased 5-HT release via antagonism of NE a2 heteroreceptors located on serotonin-

ergic neurons.


Miscellaneous Antidepressants


The mechanism of action of bupropion (Wellbutrin) is considered complex and reportedly involves a block of DA re-uptake via the dopamine transporter (DAT), but the overall antidepressant action is noradrenergic. A metabolite that contributes to the overall action and its formation can be easily rationalized. Oxidation of one of the methyl groups on the f-butyl substituent yields hydroxybupropion, an active metabolite. Reduction of the keto group also occurs, yielding threohydrobupropion and erythrohydrobupropion. Both of these metabolites are also active.

Hydroxybupropion is half as potent as the parent bupropion, and the hydrobupropion isomers are five times less potent. The presence of these metabolites, especially hydroxy-bupropion which is formed by cytochrome P450 2D6 (CYP2D6), suggests that there will be a myriad of drug interactions with bupropion.

Duloxetine (Cymbalta)

Duloxetine (Cymbalta) is a newer antidepressant. It is largely like venlafaxine, which is an SNERI (selective nor-epinephrine reuptake inhibitor).

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Eliminating Stress and Anxiety From Your Life

It seems like you hear it all the time from nearly every one you know I'm SO stressed out!? Pressures abound in this world today. Those pressures cause stress and anxiety, and often we are ill-equipped to deal with those stressors that trigger anxiety and other feelings that can make us sick. Literally, sick.

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