Pharmacology of Antidepressants and Anxiolytics PDF

L43. Drugs targeting serotonin and norepinephrine synaptic transmission: Antidepressants and anxiolytics Most drugs used in the treatment of depression and anxiety target the function of monoamine systems, and more specifically serotonin and norepinephrine, in the brain. Therefore, we begin with a b...

L43. Drugs targeting serotonin and norepinephrine synaptic transmission: Antidepressants and anxiolytics Most drugs used in the treatment of depression and anxiety target the function of monoamine systems, and more specifically serotonin and norepinephrine, in the brain. Therefore, we begin with a brief survey of these two neurotransmitters. The neurobiology of norepinephrine and serotonin in the brain Serotonergic neurons and the Raphe nuclei. The Raphe nuclei are a series of predominantly midline cell groups extending through the brainstem that contain the totality of serotoninergic neurons in the brain. These cells uniquely express the enzyme Tryptophan hydroxylase (TPH2) which converts tryptophan to 5-hydroxytryptophan (5-HTP), which is then decarboxylated by the enzyme aromatic amino acid decarboxylase (AAAD) to generate 5-hydroxytrypamine (5-HT, serotonin) (Fig. 1). As with dopamine, serotonin is synthesized in the cytoplasm and packed into vesicles by VMAT. Within the serotonergic neurons serotonin is degraded by monoamine oxidase and aldehyde dehydrogenase to generate 5-hydroxy-3-indolacetic acid (5-HIAA), the main metabolite of serotonin. Upon release from the neuronal terminals serotonin is inactivated by a combination of diffusion (dilution) and reuptake into serotonergic neurons by the serotonin transporter (SERT). Figure 1, Serotonin distribution and synthesis in the brain Upon release, serotonin acts on seven main classes of receptors, six of which are metabotropic GPCRs that couple to different G proteins - and hence activate different signaling cascades - and one that is a ligand gated ion channel (Fig. 2). Figure 2. Serotonin receptor subtypes The distribution of these receptors has been mapped in both primates and rodents using a variety of techniques. They are all present in the CNS but are differentially expressed across brain regions and cell types, with neurons frequently expressing more than one receptor subtypes (Fig. 3). Figure 3. Distribution of serotonin receptors in the brain The serotonin neurons themselves express three of these receptors that function as serotonin autoreceptors inhibiting neuronal activity (5-HT1A) and serotonin release (5-HT1B/1D). Norepinephrine neurons. The locus coeruleus is a small nucleus comprised of a few thousand neurons at the edge of the 4th ventricle in the pons (Fig. 4). It contains most of the norepinephrine releasing neurons in the brain, with the remaining located in a few sparse cell groups extending ventrally and posteriorly. The cells in these cell groups project to the entire neuroaxis and provide the totality of the norepinephrine (and epinephrine) innervation of the brain and spinal cord. Figure 4, Biosynthesis of catecholamines Like the dopamine cells of the midbrain, norepinephrine neurons express tyrosine hydroxylase, which produces L-dopa from tyrosine, and aromatic amino acid decarboxylase (AAAD), which removes the carboxy group of L-dopa to make dopamine. Norepinephrine neurons additionally express dopamine β-hydroxylase (DBH) which converts dopamine to norepinephrine. Finally, a very, very small group of cells posterior to the locus coeruleus additionally expresses phenylethanolamine-N-methyl transferase (PNMT) which leads to the production of epinephrine from norepinephrine (Fig. 4). Catecholamines are mostly synthesized in the cytoplasm and are packed into vesicles for release by the vesicular monoamine transporter (VMAT). Upon release from the neuronal terminals norepinephrine/epinephrine is inactivated by a combination of diffusion (dilution) and reuptake into adrenergic neurons by the norepinephrine transporter (NET)(Fig. 4). Norepinephrine acts on α1, α2 and β receptors to regulate the function of postsynaptic neurons. All these receptors are metabotropic G protein coupled receptors (GPCRs) and each of them couples to a different G protein signaling cascade (Fig. 5). Consequently, each regulates a different set of cellular processes. These receptors are not expressed evenly across all brain regions and cell types. Rather, they are differentially expressed across regions and cell types. Figure 5. Adrenergic receptors and their G protein coupling The norepinephrine cells themselves express α2-adrenergic receptors which in this case are g n ally f d a “au. va n f h “au ” suppresses the activity of these neurons and inhibits neurotransmitter release. Drugs for the treatment of anxiety and depression Anxiety and depression form a complex cluster of mental disorders which exhibits extensive comorbidity. Here we will not address the specific diagnostic criteria for these disorders but rather the principles of drug treatment, which tend to be common across most diagnostic classes. Figure 6 illustrates the most prescribed antidepressants for 2019, Figure 6. Most prescribed antidepressants The first clinically effective antidepressants were discovered accidentally during the 1950s during clinical trials for antituberculosis activity (iproniazid) or antipsychotic (imipramine) activity. These drugs are representative of the two main classes of first-generation antidepressants; the MAO inhibitors (MAOIs; iproniazid) and the tricyclic antidepressants (TCAs; imipramine). The MAOI are (mostly) irreversible inhibitors of the catabolic enzyme monoamino oxidase (MAO). The TCAs bind to the serotonin transporter (SERT) and/or the NE transporter (NET) to inhibit serotonin and/or norepinephrine reuptake (Fig. 7). Different TCAs preferentially target SERT or NET. Imipramine for example is about equieffective at SERT and NET while desipramine (aka desmethylimipramine) preferentially target NET. Clomipramine (aka chlorimipramine) in contrast is highly selective for SERT. TCAs are often metabolized to produce active compounds with their unique preferences for SERT or NET.  Figure 7. Mechanism of action of antidepressants TCAs and MAOIs however exhibit significant adverse effects that limit their use. Most notably, MAOIs potentiate the action of indirectly acting sympathomimetic amines, including dietary tyramine, thus risking hypertensive crisis. Isocarboxazid, phenelzine and selegiline are modern examples of this drug class but are seldom used. Similarly, TCAs exhibit activity at multiple receptors including muscarinic, α1-adrenergic, and H1 histamine. This leads to numerous adverse effects (see table 1) and again only a handful of them are still in use. Notable exceptions are Clomipramine (chlorimipramine), which remains a mainstay for the treatment of obsessive-compulsive disorder (OCD), probably due to its extraordinary potency and selectivity for SERT, and amitriptyline that has found a niche in pain management (see below). Understanding the key role of SERT in the actions of the TCAs led to the development of the Selective Serotonin Reuptake Inhibitors (SSRIs), starting with fluoxetine in the 1970s, and of the Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) about a decade later (Fig. 7). Escitalopram, fluoxetine, paroxetine, and sertraline are widely used SSRIs and good examples of this drug class. Venlafaxine and duloxetine are widely used SNRIs and good examples of this second drug class (Fig. 8). Atomoxetine is a selective norepinephrine reuptake inhibitor approved for the treatment of ADHD. Adverse effects for these are generally modest and are listed in Table 1. These drugs have milder adverse effects than TCAs (table 1) and are now the most used drug classes for the treatment of anxiety and depression.  g n a n an d an y l an d an n a n da nh nd g n a n an d an l v nn u a nh n n and n n h n u a nh hFigure an8. Drug d classesan for the treatment of anxiety and depression Importantly, none n of lthese drugs n act d aimmediately n but rather take time - generally a few weeks - to elicit their therapeutic response (Fig. 9). a u v al... y ha. Figure 9. Time course of antidepressant response (adapted from Jakubovski et al., Am. J. Psychiat. 173:174-183, 2016 ) The reason for this delay is not well understood, and not for luck of trying! In general, there is very little evidence in support of the idea that anxiety and depression reflect a defect in serotonin of norepinephrine signaling in the brain. Rather, chronic treatment with these drugs is thought to result in adaptative changes in the brain that manifest themselves in an amelioration of symptoms. One long standing view is that this hypothesized adaptative response involves changes in serotonin and or norepinephrine signaling in the brain. A more recent view is that the antidepressant/antianxiety effects reflect remodeling of central synaptic networks in response to changes in serotonin/norepinephrine tone, away from the anxiety/depressed state. One of the most exciting developments in the treatment of depression has been the realization that the NMDA receptor antagonist ketamine elicits a rapid and sustained antidepressant response (Fig. 10). Although ketamine is a dissociative anesthetic and exhibit abuse potential its S isomer esketamine was approved in 2019 for treatment-resistant depression. Figure10. Effect of ketamine on depression (Murrough et al., Am. J. Psychiat. 170:1134-1142, 2013) A fraction of patients exhibiting depression will also show mania/hypomania alternating with the depressive episodes (Fig. 11). Mania is generally treated with mood stabilizers such as carbamazepine, valproic acid or lithium, and with antipsychotics. When such patients receive antidepressant treatment, the relief of depressive symptoms can induce the onset of mania/hypomania.  Figure 11. Bipolar disorders (From Calabrese et al., Am. J. Psychiat 174:48-10, 2017) Treatment of anxiety disorders. SSRIs and SNRIs are also mainstay for the treatment of anxiety disorders including generalized anxiety disorder, panic disorder, and agoraphobia. Drugs that block SERT (e.g. Chlorimipramine, Fluoxepine, fluvoxamine, paroxetine) are also the mainstay for the treatment of obsessive-compulsive disorder (OCD). Additionally, Buspirone, a selective agonist of serotonin receptors of the 5-HT1A subtype, is similarly effective in the treatment of generalized anxiety disorder. One practical consequence of the delayed therapeutic response to these drugs is that they are not very useful for the treatment of acute anxiety. Benzodiazepines such as alprazolam and clonazepam are rapid-acting, highly effective anxiolytics that are useful in the management of anxiety. However, when administered acutely their use if associated with sedation and muscle relaxation, and their chronic use with the development of tolerance and dependence. In some cases of situational anxiety β-blockers, which block some of the more obvious autonomic manifestation of sympathetic activation, have been found to be of some usefulness. Trazodone, bupropion and mirtazapine. Trazodone was developed in the 1960s and was approved by the FDA for use in 1981 for the treatment of depression. It is now widely used, often off label, in the treatment of multiple conditions including anxiety and depression, insomnia, OCD and pain management. Trazodone binds to multiple GPCRs, including several monoamine receptors, and also to SERT. Its mechanism of action is generally attributed to blockade of 5-HT2 receptors, although that interpretation is questionable given that more selective 5-HT2 antagonist do not share its therapeutic profile. Bupropion and mirtazapine are also widely used antidepressants. They interact with multiple monoamine targets in the brain but their mechanism of action remains poorly understood. Bupropion has been found useful in supporting smoking cessation. Use of antidepressants in pain management Antidepressants are effective in the treatment of chronic pain, including neuropathic pain and migraine, even in the absence of anxiety and depression. The mechanism for this effect is not clear but is widely believed to involve an effect on descending serotonergic and noradrenergic spinal cord projections. Drugs that target both serotonin and norepinephrine reuptake are thought to be more effective in this regard and the SNRI duloxetine has been approved for the treatment of joint and muscle pain. The TCA amitriptyline is widely used (off label) for the treatment of neuropathic pain. ug u d f h a n f an yd d n da n h an d an an ly n d an nu f h a n f an ul n a yl n  Table 1. Subclass Mechanism of Clinical Pharmacokinetics Toxicities Action Applications & Drug Interactions Tricyclic antidepressants Amitriptyline, clomipramine, Block Major CYP substrates: α block, M block, imipramine, etc norepinephrine depression, interactions with sedation, weight and 5-HT gain transporters chronic pain, inducers and v d obsessive- inhibitors arrhythmias, compulsive seizures disorder L ng half-lives (OCD)— clomipramine Selective serotonin reuptake inhibitors (SSRIs) Citalopram, fluoxetine, Block 5-HT Major CYP 2D6 and 3A4 Sexual paroxetine, sertraline, etc transporters depression, inhibition dysfunction anxiety (fluoxetine, disorders, a n OCD, PMDD, fluv a n PTSD, bulimia, Half-lives: 15+ h etc Serotonin-norepinephrine reuptake inhibitors (SNRIs) Venlafaxine, Block NE and 5- Major Half-lives: 10+ h Anticholinergic, desvenlafaxine, HT transporters depression, sedation, duloxetine chronic pain, hypertension fibromyalgia, (venlafaxine) menopausal symptoms 5-HT2 antagonists Nefazodone, trazodone Block 5-HT2 Major Usually require bid da n receptors depression, d ng Y d α and hypnosis inhibition blockade (trazodone) n fa d n (trazodone) Short halflives Other heterocyclics Amoxapine, bupropion, Mirtazapine Major Extensive hepatic Lowers seizure maprotiline, mirtazapine blocks depression, a l threshold yna α smoking CYP2D6 inhibition (amoxapine, cessation (bupropion) u n mechanism of (bupropion), sedation and action of others sedation weight gain uncertain (mirtazapine) (mirtazapine) Monoamine oxidase inhibitors (MAOIs) Isocarboxazid, phenelzine, Inhibit MAO-A Major Hypertension with Hypotension, selegiline and MAO- depression tyramine and insomnia selegiline more unresponsive active vs MAO-B to other drugs sympathomimetics Serotonin syndrome if combined with SSRIs Very long half- lives MAO-A, monoamine oxidase type A; MAO-B, monoamine oxidase type B; PMDD, premenstrual dysphoric disorder; PTSD, post-traumatic stress disorder. Adapted from : Katzung &Trevor's Pharmacology: Examination &Board Review, 13e