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Chapter 26. Putative New-Generation Antidepressants

Florian Holsboer, M.D., Ph.D.
DOI: 10.1176/appi.books.9781585623860.440031

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For the past half-century, antidepressant development has been dominated by drugs that interfere with monoamine neurotransmitters. Some progress regarding safety and adverse effects is undeniable, and the increasing specificity of most current antidepressants targeting exclusively monoamines accounts for this improvement. Nevertheless, existing antidepressants exhibit limited efficacy and protracted onset of action, and we still do not know whether the pharmacological actions delineated thus far are those that account for the clinical benefits of these drugs in 60%–70% of patients with depression. Severe depression poses a particularly difficult problem, because failure to achieve clinical remission yields the risks of extended illness duration and chronicity (Nemeroff 2007). Elucidation of crucial steps in the mechanism of action of current antidepressants could yield an array of new drug candidates. The alternative route to developing better antidepressants relies on the increasing knowledge of the pathophysiology of depression emerging from clinical research and well-founded hypotheses derived from animal models. Despite huge research efforts by both academic and pharmaceutical industry investigators, none of the many discoveries of mechanisms involved in depression-related behavior has yet been translated into clinical application.

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FIGURE 26–1. Targeting stress hormone abnormalities as putative treatment options.Activation of the hypothalamic-pituitary-adrenal (HPA) system results in elevation of corticotropin-releasing hormone (CRH), vasopressin, and cortisol, which produce several signs and symptoms of depression and anxiety. Blocking the actions of these neuropeptides at the receptor level provides a new lead for antidepressant and anxiolytic drug discovery.  = increased.

FIGURE 26–2. Effects of a selective CRH1 receptor antagonist on number of entries into open arms of elevated plus-maze.Mice selectively bred for high anxiety-like behavior (HAB) assessed on the elevated plus-maze show increased CRH expression in the PVN (not shown). When HAB mice are treated with a selective CRH1 receptor antagonist, their behavior normalizes and becomes indistinguishable from that of mice with normal anxiety-like behavior (NAB). Hatched bars indicate pretreatment with the CRH1 receptor antagonist DMP-696. CRH = corticotropin-releasing hormone; CRH1 = corticotropin-releasing hormone 1 receptor; CRH2 = corticotropin-releasing hormone 2 receptor; PVN = paraventricular nucleus of the hypothalamus.Source. M. Bunck (Max Planck Institute of Psychiatry, Munich), personal communication, August 2006.

FIGURE 26–3. Results from an open-label proof-of-concept study suggest the potential usefulness of a CRH1 receptor antagonist in severely depressed patients.Two patient samples (n = 10 each) with severe major depression were treated with R 121919, a selective high-affinity CRH1 receptor antagonist. Two different dosage escalation panels with weekly increases from 5–20 mg to 40 mg (black lines) and from 40–60 mg to 80 mg (green lines) were administered, resulting in significantly decreased severity scores on both depression (Hamilton Rating Scale for Depression [Ham-D]) and anxiety (Hamilton Anxiety Scale [Ham-A]) scales. Note that after cessation of active treatment, clinical worsening of depressive and anxiety symptoms was observed. CRH = corticotropin-releasing hormone 1 receptor.Source. Adapted from Zobel et al. 2000.

FIGURE 26–4. A CRH1 receptor antagonist attenuates stress-elicited hormone response.When challenged with a psychosocial stressor, healthy subjects pretreated with the CRH1 receptor antagonist NBI-34041 showed lower secretion of ACTH and cortisol than did untreated subjects. ACTH = adrenocorticotropic hormone; CRH1 = corticotropin-releasing hormone 1 receptor; TSST = Trier Social Stress Test.Source. Adapted from Ising et al. 2007.

FIGURE 26–5. Mode of action of rolipram.Rolipram inhibits phosphodiesterase inhibitor 4 (PDE4), thus preventing degradation of cAMP into systems of 5'AMP and enhancing phosphorylation of transcriptional factors (e.g., CREB via protein kinase A [PKA]). 5'AMP = adenosine-5'-monophosphate; AC = adenylate cyclase; cAMP = cyclic adenosine monophosphate; CREB = cAMP response element binding protein; Gs = stimulatory G protein.

FIGURE 26–6. Effects of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) ligands on hippocampal neuron survival.(A) Dexamethasone (DEX), a GR agonist, induces neuronal apoptosis, while aldosterone (ALDO), an MR agonist, counteracts this effect. (B) The proapoptotic effect of dexamethasone is further increased by RU 28318, a selective antagonist of the MR. CON = control.*P <0.05 versus CON; +P <0.05 versus DEX.Source. Adapted from Crochemore et al. 2005.
Table Reference Number
TABLE 26–1. Expression of CRH and CRH receptors in the rodent central nervous system

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