Serotonin antidepressant effects

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

AS 1990). Several 5-HTlA agonists have been found to produce anxiolytic effects in animal models and in human clinical trials (File et al. 1996 Krummel and Kathol 1987 Goldberg and Finnerty 1979). Furthermore, they have antidepressant effects they augment the antidepressant effects of serotonin reuptake inhibitors, and they decrease the therapeutic latency (Bouwer and Stein 1997 Artigas et al. 1996 Sussman 1998 Rickels et al. 1991 Wieland and Lucki 1990 Jenkins et al. 1990 Fabre 1990). However, results have not been uniformly positive, such as in refractory severe depression (Sussman 1998 Fischer et al. 1998)... 

How interference with these trans-mitter/modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e 2-3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and p-adrenocep-tors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria). 

The field of antidepressant research was revolutionized in the late 1980s by the introduction of selective serotonin reuptake inhibitors (SSRIs), exemplified by fluoxetine (9). In addition to their antidepressant action, SSRIs have also proven effective for a broad range of psychiatric illnesses, and, more importantly, they demonstrated an improved tolerability profile as compared to TCAs and MAOIs due to their increased selectivity. On the other hand, SSRIs proved inferior to TCAs and MAOIs in their reduced antidepressant effects, slower onset of action, lower remission rates, and decreased ability to control the physical symptoms associated with depression. 

Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or moclobemide) in major depressions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is responsible for the antidepressant properties of these agents. However, since complete MAO-A inhibition is achieved clinically within a few days of treatment, while the antidepressant effects of these drugs are not observed for 2 to 3 weeks, suggests that additional actions must be involved. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitfers, such as norepinephrine and serotonin, at CNS presynaptic membranes, increasing their availability at postsynaptic receptor sites. The metabolite, 7-OH-amoxapine has significant dopamine receptor blocking activity similarto halo-peridol. Therapeutic Effect Produces antidepressant effects. 

Mechanism of Action An antidepressant and antiobsessive agent that selectively inhibits neuronal reuptake of serotonin. Therapeutic Effect Relieves depression and symptoms of obsessive-compulsive disorder. 

MecfianismofAction An antidepressant that inhibits the MAO enzyme system at central nervous system (CNS) storage sites. The reduced MAO activity causes an increased concentration in epinephrine, norepinephrine, serotonin, and dopamine at neuron receptor sites. Therapeutic Effect Produces antidepressant effect. 

Mechanism of Action A mood stabilizer that affects the storage, release, and reuptake of neurotransmitters. Antimanic effect may result from increased norepinephrine re-uptake and serotonin receptor sensitivity. Therapeutic Effect Produces antimanicand antidepressant effects. 

Mechanism of Action A tricyclic antidepressant that increases synaptic concentration of norepinephrine and/or serotonin by inhibiting their reuptake by presynaptic membranes. Therapeutic Effect Produces antidepressant effect. 

Lithium has numerous pharmacologic effects. It is able to cross through sodium channels, competing with monovalent and divalent cations in cell membranes (AHFS, 2000). Animal studies have shown that lithium at a serum level of 0.66 + — 0.08 mEq/L can increase the amphetamine-induced release of serotonin (5-hydroxytryptamine [5-HT]) and the concentrations of a serotonin metabolite (e.g., 5-hydroxyindoleacetic acid [5-HIAA]) in the perifornical hypothalamus (PFH) of rats before and after chronic lithium chloride administration (Baptista et ah, 1990), a mechanism possibly involved in lithium s antidepressant effect. The precise neurobiological mechanisms through which lithium reduces acute mania and protects against recurrence of illness remain uncertain (Lenox and Hahn,... 

Danish University Antidepressant Group Paroxetine a selective serotonin reuptake inhibitor showing better tolerance but weaker antidepressant effect profile in comparison with clomipramine a controlled multicentre study. J Affect Disord 18 289-299, 1990... 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

In contrast to the SSRIs, venlafaxine has an ascending dose-response curve consistent with its sequential, concentration (and hence dose) dependent effects on serotonin and NE uptake pumps (Table 7-9). At 225 mg per day, the magnitude of the antidepressant effect is 50% higher than that seen with the SSRIs. Also consistent with its dual mechanism of action at higher concentrations, venlafaxine at a dose of 225 mg per day produced an antidepressant response in hospitalized patients with melancholia superior to both placebo and fluoxetine (114, US, 116, H7, H8, H9, 120, 121, 122, 123, 124,125, 126,127, 128,129, 130,131, 132,... 

Nefazodone has some unusual pharmacological properties, not only inhibiting serotonin uptake, but also blocking the 5-HT 2a receptor. It may be that the antidepressant effect of serotonin agents is due to mediation of 5-HT transmission in the absence (or even the blockade) of 5-HT2a transmission. As a result of these actions, nefazodone is even more specific in terms of affecting a subtype of serotonin receptor than are the SSRIs or venlafaxine. 

Serotonin potentiation has also been postulated as a possible mechanism, given that tryptophan depletion may reverse the antidepressant effects of light therapy... 

FIGURE 6—28. Therapeutic actions of the tricyclic antidepressants—part 1. In this diagram, the icon of the TCA is shown with its serotonin reuptake inhibitor (SRI) portion inserted into the serotonin reuptake pump, blocking it and causing an antidepressant effect. 

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