Monoamines are connected to the pathophysiology of depression. Symptoms may occur because concentrations of neurotransmitters, such as<unk>  and serotonin, are insufficient, leading to downstream changes. Medications for depression affect the transmission of serotonin,<unk> , and dopamine. Older and more unselective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of<unk>  and serotonin in the brain, which results in higher concentrations of neurotransmitters. Antidepressants that have dual mechanisms of action inhibit the reuptake of both serotonin and<unk>  and, in some cases, inhibit with weak effect the reuptake of dopamine. Antidepressants affect variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity {source needed}. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression. Drugs that selectively block the reuptake of serotonin and<unk>  effectively treat depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity. Tricyclic antidepressants Inhibiting the reuptake transport protein results in increased concentrations of serotonin and<unk>  in the synaptic clefts, leading to improvement of depression symptoms. TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on<unk>  reuptake transporters and serotonin reuptake transporters. Increased<unk>  and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for<unk>  reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites. In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of<unk>  in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of<unk>  transport and variable blockade of serotonin transport.<unk>  interacts with postsynaptic α and β adrenergic receptor subtypes and presynaptic α2 autoreceptors. The α2 receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of<unk>  is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylase, an effect mediated by decreased cyclic AMP-mediated phosphorylation-activation of the enzyme. α2 receptors also cause decreased intracellular cyclic AMP expression which results in smooth muscle relaxation or decreased secretion. TCAs activate a negative feedback mechanism through their effects on presynaptic receptors. One probable explanation for the effects on decreased neurotransmitter release is that, as the receptors activate, inhibition of neurotransmitter release occurs (including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents). Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release, but repeated administration of TCAs finally leads to decreased responses by α2 receptors. The desensitization of these responses may be due to increased exposure to endogenous<unk>  or from the prolonged occupation of the<unk>  transport mechanisms (via an allosteric effect). The adaptation allows the presynaptic synthesis and secretion of<unk>  to return to, or even exceed, normal levels of<unk>  in the synaptic clefts. Overall, inhibition of<unk>  reuptake induced by TCAs leads to decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters. TCAs do not block dopamine transport directly but might facilitate dopaminergic effects indirectly by inhibiting dopamine transport into noradrenergic terminals of the cerebral cortex. Because they affect so many different receptors, TCAs have adverse effects, poor tolerability, and an increased risk of toxicity. Selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants. With increased receptor selectivity compared to TCAs, undesired effects such as poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood–brain barrier. Serotonergic pathways are classified into two main ways in the brain: the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord. Selective<unk>  reuptake inhibitors Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental. With administration of<unk> s, neuronal activity in locus coeruleus region is induced because of increased concentration of<unk>  in the synaptic cleft. This results in activation of α2 adrenergic receptors, as discussed previously. Assays have shown that<unk> s have insignificant penchant for mACh, α1 and α2 adrenergic, or H1 receptors. Dual serotonin and<unk>  reuptake inhibitors Agents with dual serotonin and<unk>  reuptake inhibition <unk> s) are sometimes called non-tricyclic serotonin and<unk>  reuptake inhibitors. Clinical studies suggest that compounds that increase the concentration in the synaptic cleft of both<unk>  and serotonin are more successful than single acting agents in the treatment of depression, but the data is not conclusive whether<unk> s are a more effective treatment option over SSRIs for depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters, which have low adverse effects compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRIs alone, which give the impression that synergism is an efficient property in mediating antidepressant activity. The non-tricyclic<unk> s have several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic<unk> s. Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.
Serotonin–norepinephrine reuptake inhibitor
Serotonin–dopamine reuptake inhibitor
Norepinephrine reuptake inhibitor
Glycine reuptake inhibitor
Dopamine reuptake inhibitor
Monoamine reuptake inhibitor
Serotonin–norepinephrine–dopamine reuptake inhibitor
Excitatory amino acid reuptake inhibitor