The clinical description of depression is complex, covering a broad range of symptoms that lack a unifying biological hypothesis. Depression has both genetic and environmental components, with linkage studies suggesting it is a polygenic disor-der.131 Here again, effective therapeutics are contributing to an understanding of its underlying molecular mechanisms.132 Modern treatment for depression, which focuses exclusively on agents that modulate monoamine neurotransmission, began with a monoamine oxidase inhibitor (MAOI) originally developed to treat tuberculosis. MAOIs increase serotonin and norepinephrine concentrations in the brain by inhibiting the MAO enzyme. They are highly effective in treating depression but are used only rarely due to potentially dangerous drug interaction effects.

A second breakthrough in depression treatment came from derivatives of chlor-promazine, developed as potential antipsychotics. One such derivative, imipramine (Figure 7.2), failed to show benefits in schizophrenic patients but was remarkably effective in patients who had severe depression.133 Imipramine, still in use today, is a tricyclic antidepressant (TCA) that acts by inhibiting cellular reuptake mechanisms for norepinephrine and serotonin to increase activity within these GPCR families.134 Imipramine retains some activity at GPCRs, including antagonism at histamine H1, muscarinic, and a-1 adrenergic receptors, but this activity contributes to an unattractive side-effect profile. Recent developments include selective serotonin reuptake inhibitors (SSRIs), serotonin + norepinephrine reuptake inhibitors (SNRIs), and norepinephrine + dopamine reuptake inhibitors (NDRIs), implicating multiple NT pathways in the spectrum of disorders that comprise major depression.135

Until now, GPCRs played only minor roles as direct drug targets in the treatment of depression, mediating the effects of some atypical or "second generation" antidepressants such as mirtazapine, which has antagonist activity at 5HT2 and a-2

receptors and at the 5HT3 ligand-gated ion channel receptor, and nefazodone, which blocks 5HT2 receptors in addition to 5HT reuptake.135 5HT1A receptor agonism has been proposed to help alleviate depression, anxiety, negative symptoms, and cognitive dysfunction.136 5HT2C receptor ligands may provide anti depressive activity through disinhibition of the mesolimbic dopamine system.92 GPCRs feature more prominently, however, in a new wave of emerging therapies aiming to address deficits of current therapies including slow onset of action, inability to achieve full remission, difficulty targeting significant populations of nonresponding patients, and minimization of residual side effects including sexual dysfunction.

Several new therapeutics target neuropeptide GPCRs that mediate stress responses.137 Previous interest was focused on the NK1 neurokinin receptor, which mediates highly diverse effects of substance P.138 139 A direct association of NK1 receptors with depression has been demonstrated in guinea pig and gerbil models140 and by behavioral studies in NK1 receptor knockout mice.141 In recent clinical trials, two highly selective NK1 receptor antagonists, aprepitant142 and L-759274,143 have shown good tolerability and efficacy for major depression. Sustained activation of stress systems has been implicated in pathophysiology in some depressed patients.144 Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in depressive disorders,145 with excess levels of the cortisol stress hormone detected in about 50% of patients with moderate to severe depression. This led to interest in the corticotrophin-releasing factor (CRF) receptor antagonist R-121919 that has shown efficacy in preclinical models and in a small clinical trial for major depression.146

Other neuropeptide receptors including neuropeptide Y, melanocortin-concen-trating hormone, and vasopressin V1b receptors, in addition to dopamine, canna-binoid, and 5-opioid receptors, have also been implicated in the pathophysiology of depression.134 New approaches within the monoaminergic systems may be possible.147 For example, modulation of serotonin autoreceptors may provide a quicker onset of action for reuptake inhibitors. Neuroprotection, neurogenesis, and neuroim-mune system modulation are additional research areas for major depression in which GPCRs may emerge as targets.137

How to Stop Your Depression Now

How to Stop Your Depression Now

Finally, Retired Clinical Counsellor Reveals the Secrets Successful Psychiatrists and Psychologists Don't Want You to Know. How to Stop Your Depression Now Reclaim Yourself and Live Again Get the Depression Busting Tools You Need To Win the War Against Depression. Depression is an illness that many people often sweep under a rug. However if depression is left untreated... Your life can become a living nightmare. Depression is a growing epidemic in the US, but it never gets the urgent attention it deserves. You need help and you need it now.

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