Antidepressants neurochemical effects

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

The neurochemical effects of the tricyclic antidepressants are blockade of the re-uptake of norepinephrine and for some drugs also serotonin by nerve terminals in the CNS and peripherally. This reuptake inhibition results in higher concentrations of the neurotransmitters at their receptors sites. There is little or no effect on DA neurotransmission. The tricyclic antidepressants have varying affinities for U2... 

Georgotas A et al Trazodone hydrochloride A wide spectrum antidepressant with a unique pharmacological profile. A review of its neurochemical effects, pharmacology, clinical efficacy, and toxicology. Pharmacotherapy 1982 2(5) 255. [PMID 6763207]... 

Loftier et al. 2006). Coadministration of sulpiride and fluvoxamine, a serotonin reuptake inhibitor, increased in vivo dopamine release in the prefrontal cortex of rats (Ago et al. 2005a). The increase probably is the neurochemical counterpart of the antidepressant-like effect of coadministration of sulpiride and fluvoxamine in mice, as measured in the tail suspension test (Ago et al. 2005b). A recent clinical trial showed superior antidepressant efficacy of the combination of sulpiride plus the serotonin reuptake inhibitor paroxetine compared with paroxetine alone and, importantly enough, an accelerated antidepressant response of the combination (Uchida et al. 2005). 

However, these neurochemical effects are acute. That is to say, biogenic amine reuptake is blocked within minutes of drug administration. The therapeutic effects, on the other hand, in ameliorating or reversing the symptoms of major depression, require repeated antidepressant drug administration. Though some improvement in symptoms is often noted during the... 

The psychopharmacological profile of minaprine in mice and rats has been investigated in comparison with reference antidepressant drugs [133, 138], Additional reports on various biological effects of minaprine [14, 139-143], and recent discussions of its neurochemical profile are available [144, 145]. 

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Preliminary results from case reports, case series, and open and increasingly better controlled trials have found TMS to be effective in the treatment of depression. TMS, antidepressants, and ECS appear to induce similar effects in animal behavioral models of depression and changes in brain neurochemical activity. These include changes in the forced swim test, increase in seizure threshold, and effects on b-noradrenergic receptor downregulation. Whereas seizures appear unnecessary to achieve clinical benefit with TMS, it is still unclear what aspects are beneficial. As noted earlier, although this modality is associated with some complications (e.g., headaches and, rarely, inadvertent seizure) relative to ECT and perhaps even pharmacotherapy under certain situations, it appears to be quite safe. Future studies of major depression should explore TMS-related issues such as the following ... 

Marshall DL, Redfern PH, Wonnacott S (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis comparison of naive and chronic nicotine-treated rats. J Neurochem 68 1511-19 Mongeau R, Blier P, De Montigny C (1997) The serotonergic and noradrenergic systems of the hippocampus their interactions and the effects of antidepressant treatments. Brain Res Rev 23 145-95... 

Bupropion, the only marketed aminoketone antidepressant, appears to have a unique mechanism of drug action. It has no appreciable effect on the reuptake of NE or 5-HT, and its most potent neurochemical action is blockade of DA reuptake. 

Studies clearly support that the neurochemical-based treatments for depression such as antidepressant medications and ECT are effective in lifting depressed moods. Controlled studies using neurochemically based treatments specifically for the treatment of major depression indicated that 78% of the depressed individuals improved with ECT, and 70% with the newer antidepressants medications (Maxmen Ward, 1995). In practice, it is estimated that 50% of individuals who take antidepressant medicines report feeling better or achieve complete remission. In addition, antidepressant medications can be used to treat related conditions such as obsessive compulsive disorder and overwhelming anxiety (Brophy, 1991). Antidepressants are often used to treat excessive anxiety since they can block the symptoms of panic including rapid heartbeat, terror, dizziness, chest pains, nausea, and breathing problems. 

Introduced in 1988, Prozac is the oldest in the SSRI class and is still the most commonly prescribed (Morris, 1999). Prozac is a highly successful antidepressant that has revolutionized the treatment of depression because of its ability to raise serotonin levels in the brain. Increased availability of this neurochemical has been directly related to addressing effectively the symptoms prevalent in depression, and Prozac was recently approved to treat obsessive-compulsive disorder and the eating disorder bulimia. Prozac and the other SSRIs are also considered the medication of choice for working with depressed older individuals because of fewer side effects than the tricyclic medications (Haider Miller, 1993). In 1999 Prozac was endorsed by the FDA as being especially effective for geriatric depression (Hussar, 2000). 

Saint-John s-wort is one example of a natural herbal remedy for depression that has recently gained in popularity and prevalence across the United States. In Europe, it is reportedly outselling the prescription medication Prozac. Saint-John s-wort (Hypericum perforatum) is a lush green herb with bright yellow flowers that has traditionally been used to heal wounds and as a tea to soothe nerves and relieve melancholy. The natural antidepressant effect that results enhances the neurochemical serotonin, norepinephrine, and dopamine with few side effects (Lemonick, 1997). 

A third generation of antidepressants will be needed to advance into an era of higher selectivity to yield even safer and especially more effective compounds. The roadblock may well be still insufficient neurochemical knowledge. Even though the second-generation drugs discussed are safer than were the early compounds, their impact therapeutically... 

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