Monoamine oxidase A (MAOA) is an enzyme involved in the metabolism of the monoamines, eg 5-HT and noradrenaline. It converts the monoamines into their corresponding carboxylic acid via an aldehyde intermediate. MAOA regulates both the free intraneuronal concentration and the releasable stores of 5-HT and noradrenaline. MAOA inhibitors, such as phenelzine, bind to and inhibit MAOA, preventing monoamine degradation. This results in greater stores of monoamines available for release. MAOA inhibitors are used in the treatment of depression. People with depression have lower than normal levels of the monoamines and MAOA inhibitors restore the levels to within the normal range.
Depression is associated with reduced levels of the monoamines in the brain, such as noradrenaline. The selective noradrenaline re-uptake inhibitors (NARIs) are thought to restore the levels of noradrenaline in the synaptic cleft by binding at the noradrenaline re-uptake transporter preventing the re-uptake and subsequent degradation of noradrenaline. This re-uptake blockade leads to the accumulation of noradrenaline in the synaptic cleft and the concentration of noradrenaline returns to within the normal range. This action of NARIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the NARI, small amounts of noradrenaline continue to be degraded in the synaptic cleft.
When a nerve impulse arrives at a noradrenaline nerve terminal, noradrenaline is released from synaptic vesicles into the synaptic cleft. Noradrenaline molecules bind to their receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending on the specific receptor. Noradrenaline molecules are then released from their receptors and taken back into the nerve terminal via the noradrenaline re-uptake transporter. Noradrenaline is degraded by MAO and COMT, these are found in both the synaptic cleft and in the nerve terminal.
Depression is associated with reduced levels of monoamines in the brain. Noradrenergic and specific serotonergic antidepressants (NaSSAs), such as mirtazapine, have a dual mechanism of action that increases the concentration of 5-HT and noradrenaline in the synaptic cleft to within the normal range. NaSSAs bind to and inhibit both noradrenaline a2-autoreceptors and noradrenaline a2-heteroeceptors. This action prevents the negative feedback effect of synaptic noradrenaline on 5-HT and noradrenaline neurotransmission, and neurotransmission sustained. NaSSAs also block 5-HT2 and 5-HT3 receptors on the post-synaptic membrane, which causes enhanced 5-HT1 mediated neurotransmission.
When a nerve impulse arrives at a 5-HT or noradrenaline nerve terminal the neurotransmitter is released from the synaptic vesicle into the synaptic cleft. Neurotransmitter molecules bind to their specific receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending on the receptor type. 5-HT and noradrenaline molecules are then released from their receptors and taken back into the nerve terminal via either the 5-HT or noradrenaline re-uptake transporters. 5-HT and noradrenaline are degraded by MAO and COMT, these enzymes are found in both the synaptic cleft and in the nerve terminal.
Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The selective 5-HT and noradrenaline re-uptake inhibitors (SNRIs) are thought to restore the levels of 5-HT and noradrenaline in the synaptic cleft by binding at their re-uptake transporters preventing the re-uptake and subsequent degradation of 5-HT and noradrenaline. This re-uptake blockade leads to the accumulation of monoamines in the synaptic cleft and the concentration returns to within the normal range. This action of SNRIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the SNRIs, small amounts of 5-HT and noradrenaline continue to be degraded in the synaptic cleft.
When a nerve impulse arrives at a 5-HT or noradrenaline nerve terminal the neurotransmitter is released from the synaptic vesicle into the synaptic cleft. Neurotransmitter molecules bind to their specific receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending on the receptor type. 5-HT and noradrenaline molecules are then released from their receptors and taken back into the nerve terminal via either the 5-HT or noradrenaline re-uptake transporters. 5-HT and noradrenaline are degraded by MAO and COMT, these enzymes are found in both the synaptic cleft and in the nerve terminal.
Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The selective 5-HT re-uptake inhibitors (SSRIs) are thought to restore the levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter preventing the re-uptake and subsequent degradation of 5-HT. This re-uptake blockade leads to the accumulation of 5-HT in the synaptic cleft and the concentration of 5-HT returns to within the normal range. This action of SSRIs is though to contribute to the alleviation of the symptoms of depression. In the presence of the SSRI, small amounts of 5-HT continue to be degraded in the synaptic cleft.
When a nerve impulse arrives at a 5-HT nerve terminal, 5-HT is released from synaptic vesicles into the synaptic cleft. 5-HT molecules bind to their receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending on the specific receptor. 5-HT molecules are then released from the receptors and taken back into the nerve terminal via the 5-HT re-uptake transporter. 5-HT is degraded by MAO and COMT, these are found in both the synaptic cleft and in the nerve terminal.
Monoamine oxidase B (MAOB) is an enzyme involved in the metabolism of dopamine. It converts dopamine to its corresponding carboxylic acid via an aldehyde intermediate. MAOB regulates both the free intraneuronal concentration of dopamine and the releasable stores. MAOB inhibitors, such as selegiline, bind to and inhibit MAOB, preventing dopamine degradation. This results in greater stores of dopamine available for release. MAOB inhibitors are used in the treatment of depression. People with depression have lower than normal levels of dopamine and MAOB inhibitors restore the levels to within the normal range.
Tricyclic antidepressants (TCAs) are an important group of antidepressants in clinical use; they include imipramine, clomipramine, amitriptyline and desipramine. The main effect of TCAs is to block the uptake of monoamines by nerve terminals, by competing for the binding site of the carrier protein. Most TCAs are non-selective and inhibit noradrenaline and 5-HT uptake to a similar degree, but have much less effect on dopamine uptake. TCAs produce a number of side effects, mainly due to interference with autonomic control, including atropine-like effects (muscarinic cholinergic receptor block), postural hypotension (α1-adrenergic receptor block) and sedation (H1 histamine receptor block). Poor dental health, due to effects of TCAs on salivary secretion, is a common problem among middle-aged and elderly patients.
Drugs of the monoamine oxidase inhibitor (MAOI) type were among the first to be introduced clinically as antidepressants. They are now largely superseded by other types of antidepressants with improved efficacies and fewer side effects. Important examples are phenelzine and tranylcypromine. These bind covalently to the monoamine oxidase enzyme, resulting in non-competitive, irreversible inhibition; however, they do not distinguish between the two isozymes (MAO-A, MAO-B). Studies have demonstrated that the therapeutic effect of MAOIs is associated with MAO-A inhibition. This led to the development of moclobemide, which functions as a reversible, competitive inhibitor of MAO-A (RIMA). Clorgyline, although MAO-A-selective, is an irreversible inhibitor of the enzyme. The unwanted side effects of MAOIs include hypotension; atropine-like side effects (sympathomimetic effect); weight gain; and excessive CNS stimulation. The side effects associated with moclobemide are much milder than those reported with other MAOIs; they are also transient and disappear when treatment stops.
Mirtazapine is a new antidepressant that enhances both noradrenergic and serotonergic activity and is currently the only member of the noradrenergic and specific serotonergic antidepressant (NaSSA) class. It exerts its effects by blocking α2 auto- and hetero-receptors, which results in enhanced release of noradrenaline from noradrenergic terminals and increased 5-HT release from serotonergic terminals. The increase in 5-HT transmission is specifically mediated via 5-HT1 receptors, as mirtazapine selectively antagonises 5-HT2 and 5-HT3 receptors. The most common side effects are sedation (H1 histamine receptor block) and increased appetite with weight gain. Dry mouth is also common, but other anticholinergic features such as blurred vision and urinary retention are not, suggesting a symapthomimetic effect. Reboxetine exhibits specificity for inhibiting the noradrenaline re-uptake transporter and is known as a noradrenaline re-uptake inhibitor (NARI). Common side effects seen with reboxetine are atropine-like side effects (sympathomimetic effect) and allergic rashes.
Drugs of the selective serotonin re-uptake inhibitor (SSRI) type include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. These are currently the most commonly prescribed antidepressants. In addition to showing selectivity with respect to 5-HT over noradrenaline uptake inhibition, they are as efficacious as tricyclic antidepressants but without the anticholinergic side-effects. The unwanted effects of SSRIs include nausea, anorexia, insomnia and sexual dysfunction; caused by stimulation of different subtypes of 5-HT receptor.
Different types of antidepressants inhibit the re-uptake of noradrenaline and 5-HT with different potency (IC50 value). The lower the IC50 value, the more potent the drug. Secondary amine tricyclic antidepressants (TCAs), such as desipramine and nortriptyline, are relatively selective inhibitors of noradrenaline re-uptake. For example, desipramine is about 150-fold more potent as an inhibitor of noradrenaline re-uptake (IC50 = 2) than 5-HT re-uptake (IC50 = 300). In vitro, tertiary amine TCAs, such as amitriptyline and imipramine, are slightly more potent inhibitors of noradrenaline re-uptake than 5-HT re-uptake; however, they do not exhibit any selectivity in vivo. As their class names imply, noradrenaline re-uptake inhibitors (NARIs) and selective serotonin re-uptake inhibitors (SSRIs) are selective inhibitors of noradrenaline and 5-HT re-uptake, respectively. The SSRI paroxetine inhibits re-uptake of 5-HT (IC50 = 1) about 70-fold more potently than noradrenaline re-uptake (IC50 = 70). Although classed as a ‘nonselective’ reu-ptake inhibitor, in vitro venlafaxine is a more potent blocker of 5-HT re-uptake than noradrenaline reuptake. Mirtazapine is a very weak inhibitor at both noradrenaline and 5-HT re-uptake sites. It exerts its effects by antagonising α2-adrenoceptors.
The side effects produced by many of the antidepressant drugs arise from their ability to block muscarinic cholinergic receptors, H1 histamine receptors and α1-adrenergic receptors. The affinity (Ki) of a drug for a specific receptor is defined as the concentration of drug needed to occupy 50% of the available receptors; the lower the Ki value, the more potently the receptor is blocked. Many antidepressants block muscarinic cholinergic receptors causing side effects such as; dry mouth, blurred vision, constipation and urinary retention. The tricyclic antidepressants (TCAs) as a class block these receptors more potently than other types of antidepressant, and they are all associated with these side effects. Postural hypotension is associated with blockade of α1-adrenoceptors and this side effect is often seen with TCAs due to their relatively high affinity at these receptors. Histamine H1 receptor blockade causes sedation and drowsiness. Given the high affinity of mirtazapine for H1 receptors it is not surprising that many patients taking this medication report drowsiness and sedation. These side effects are not frequently observed with selective 5-HT re-uptake transporters, reboxetine or venlafaxine due to low affinity at H1 receptors.
The antidepressant nefazodone is thought to alleviate some of the symptoms of depression by inhibiting the re-uptake of 5-HT and acting as an antagonist at 5-HT2 receptors. Antagonism of noradrenaline α1 receptors leads to some of the adverse effects associated with nefazodone treatment, such as postural hypotension.
The antidepressant nefazodone is thought to alleviate some of the symptoms of depression by enhancing 5-HT neurotransmission. Ii inhibits the re-uptake of 5-HT and acts as an antagonist at 5-HT2 receptors. These two mechanisms may enhance 5-HT1A mediated neurotransmission. Nefazodone also weakly inhibits the re-uptake of noradrenaline. Two of the three metabolites of nefazodone (hydroxynefazodone and m-chlorophenylpiperazine) have similar affinities to the parent compound.
Tricyclic antidepressants (TCAs) are a group of drugs used to treat affective, or ‘mood’, disorders. Despite being an important group of antidepressant drugs they are not ideal, due to a number of unwanted side effects. Side effects of the TCAs include sedation, caused by histamine H1 receptor blockade; postural hypotension, due to α adrenoreceptor blockade; and blurred vision, dry mouth and constipation, due to muscarinic acetylcholine receptor blockade.
Tricyclic antidepressants (TCAs) are a group of drugs used to treat affective, or ‘mood’, disorders. Mood disorders are associated with reduced levels of monoamines in the brain. TCAs binding to 5-HT and noradrenaline re-uptake transporters prevents the re-uptake of these monoamines from the synaptic cleft and their subsequent degradation. This re-uptake blockade leads to the accumulation of 5-HT and noradrenaline in the synaptic cleft and the concentration returns to within the normal range.