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synopsis of new treatments of the future

Posted by jrbecker on March 10, 2003, at 19:30:30

The following is a very general synopsis of treatments in the pipeline. Seemed interesting enought to post...

Treatment of mood disorders

Charles B. Nemeroff & Michael J. Owens

Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, Georgia 30322, USA
Correspondence should be addressed to C B Nemeroff. e-mail:

Depression is a leading cause of morbidity and mortality, and its treatment includes a high percentage of the medications prescribed by physicians. Available antidepressant drugs are safe and effective, but less than half of all patients attain complete remission after therapy with a single antidepressant. Others exhibit partial, refractory or intolerant responses to treatment, emphasizing the need to discover new antidepressants. The mechanisms of action of available medications are directing the field toward new research avenues. This review highlights those areas we believe will influence the field and soon lead to better treatment.

Depression is one of the most prevalent and costly brain diseases. In the last major epidemiology study conducted in the United States1, major depression had an overall lifetime prevalence rate of 17.1% (21% in women and 13% in men), and comparable figures have been obtained worldwide. These findings represent an increase of approximately 6% in the 15 years since the previous study2. Although space constraints preclude further discussion of bipolar disorder (also known as manic–depressive illness), another 1.3–1.8% of the population is afflicted with this disorder.

Affective disorders account for considerable psychiatric morbidity (pain and suffering), but also significant disability and consequent loss of productivity. Depression has been estimated to be the second leading cause of disability worldwide, surpassed only by ischemic heart disease3. Moreover, depression is often associated with comorbid psychiatric disorders, most notably anxiety disorders (panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive–compulsive disorder and post-traumatic stress disorder). The mean age of onset of depression has markedly decreased from the 40- to 50-year-old range noted several years ago to the 25- to 35-year range, and this phenomenon has been observed worldwide4. Depression often goes undetected, especially in children, adolescents and the elderly. Mood disorders are associated with a significant risk for suicide, which remains one of the top ten causes of death in the United States and in many countries throughout the world. Depression is a major independent risk factor for the development of coronary artery disease and stroke, and possibly other major medical disorders5. The presence of depression after myocardial infarction is associated with a markedly diminished survival rate over the 18 months after the initial episode6, 7. The precise pathophysiology of mood disorders remains obscure, as does the neurobiology of normal mood regulation. However, recent advances in neuroscience, particularly in molecular neurobiology and functional brain imaging, are rapidly advancing our understanding of the biological substrates of normal and pathological mood states.

Three treatments for depression have shown unequivocal effectiveness: antidepressants, certain forms of psychotherapy and electroconvulsive therapy (ECT). Pharmacotherapy is still based almost exclusively on the serendipitous discovery that drugs that enhanced monoamine transmitter function were effective agents. Only recently has evidence arisen that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the central nervous system, particularly serotonin (5-HT) and norepinephrine (NE). It should be noted that virtually all approved classes of antidepressants act in one of three ways: (1) blockade of presynaptic monoamine transporter proteins, which remove released transmitter from the extracellular space, (2) inhibition of monoamine oxidase, which degrades monoamine neurotransmitters or (3) inhibition or excitation of pre- or postsynaptic receptors that regulate monoamine transmitter release and/or neuronal firing rates.

Although the protein targets of these drugs are known and their effects within the CNS occur almost immediately, the vast majority of patients do not respond until 3–5 weeks after the initiation of treatment. This observation has led to the almost universal view that although monoamine systems are integral to the mechanism of action of antidepressants, they are not the final common pathway of action. Identifying such pathways represents one future direction in the pharmacotherapy of mood disorders. The mechanism of action of ECT remains obscure, but it generally works more rapidly than currently available antidepressants, suggesting that discovery of more rapidly acting agents is plausible. Finding these novel targets might involve recently developed techniques in genomics and proteomics, which would allow for large-scale screening of transcripts and proteins associated with mood disorders. However, although single gene mutations can result in complex phenotypes, mood disorders appear to be multifaceted8, complicating such studies. One potential set of targets is proteins involved in synaptic plasticity; notably the transcription factor CREB and brain-derived neurotrophic factor (BDNF) are affected by many antidepressants9, 10.

Three major areas in antidepressant pharmacotherapy need improvement. The first is efficacy. After 6–8 weeks, only 35–45% of patients treated with standard doses of the most commonly used antidepressants return to premorbid levels of functioning without any significant depressive symptoms11, 12. The remainder are improved but not well, or do not respond at all. Second is the issue of tolerability. The newer generation of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are clearly superior to the older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors in terms of tolerability; overdose is not lethal, and no adverse cardiac effects occur. However, they are not without their own problematic side effects, including sexual dysfunction. Third, as noted above, the slow response to treatment makes a more rapid action a desirable attribute for novel antidepressants. Although the development of therapeutic agents that act on novel targets is probably more than 10 years away, potentially useful approaches exist in the near future, possibly by the end of this decade.

Monoamine neurotransmitters
As noted earlier, 5-HT and NE circuits are involved in mood disorders13, 14, and dysregulation of dopamine (DA) may be as well15. Drugs that selectively antagonize 5-HT, NE and possibly DA transporters are effective antidepressants. Agents selective for the serotonin transporter (fluoxetine, citalopram, fluvoxamine) are the most widely used, but the ability to antagonize additional transporters has been suggested to provide increased efficacy, a superior response in treatment-refractory patients, and a broader therapeutic spectrum across several anxiety disorders12, 16. This may account for reports that dual-acting TCAs, which inhibit both 5-HT and NE transporters in vivo, are more effective than SSRIs16. Venlafaxine and paroxetine at the upper end of their dose range clearly inhibit both 5-HT and NE reuptake17. Sertraline at the higher end of the dosage range may act as a dual 5-HT and DA reuptake inhibitor18. Duloxetine, a potent 5-HT and NE reuptake inhibitor, will almost certainly be approved soon by the U.S. FDA for the treatment of depression. Milnacipran, a dual 5-HT and NE reuptake inhibitor approved for the treatment of depression in France, Japan and other countries, is being developed in the U.S. market for the treatment of fibromyalgia as a collaboration between Pierre Fabre and Cypress Biosciences. Because of evidence that DA neurons are involved in the pathophysiology of depression, focus on DA reuptake inhibitors has intensified, and the search for compounds that antagonize all three monoamine transporters is underway.

Long-term treatment of laboratory animals with a variety of different antidepressants leads to augmented serotonergic neurotransmission, which most likely is mediated, at least in part, through an action on postsynaptic 5-HT1A receptors. Thus, 5-HT1A agonists (flesinoxan, 6-hydroxybuspirone, ipsapirone, gepirone) represent a novel class of antidepressants. Although the theoretical basis for this approach is strong, results with these agents have been disappointing, for several possible reasons. First, long-term 5-HT1A agonist administration may cause downregulation of 5-HT1A receptors. Second, some of these agents are partial agonists and may not achieve the complete receptor response that may be necessary. Third, the necessary percentage of receptor occupancy may not be obtained. Fourth, other 5-HT receptors in addition to the 5-HT1A receptor may need to be activated to achieve an antidepressant effect. Long-term treatment with SSRIs enhances serotonergic neurotransmission. Vilazodone, a 5-HT reuptake inhibitor/5-HT1A partial agonist, is being developed as an antidepressant by GlaxoSmithKline.

An alternative approach, perhaps counterintuitive, has also been suggested, namely the combination of a 5-HT1A receptor antagonist with an SSRI, the former to block presynaptic autoreceptors that normally reduce serotonergic neuronal activity. Such drugs should increase the proserotonergic effects of SSRIs. Some reports indicated positive effects with pindolol, a 5-HT1A and -adrenergic receptor antagonist19, whereas other studies found that the drug did not improve the rapidity of efficacy, perhaps due to insufficient occupancy of the 5-HT1A autoreceptor at the dose used20.

Changing the pharmacokinetic profiles of existing drugs has also proven beneficial. For example, controlled or sustained-release preparations of venlafaxine, bupropion and paroxetine are now available, and methods to deliver a monoamine oxidase inhibitor and lithium via patch technology have been developed. These methods improve tolerability of the drug, as well as patient compliance.

Novel antidepressant classes
A substantial percentage of depressed patients show hypercortisolemia—excess glucocorticoid secretion, primarily cortisol in humans, from the adrenal gland. Other measures of hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, such as non-suppression of cortisol after administration of the synthetic glucocorticoid dexamethasone, are also seen. This critical endocrine axis is controlled by hypothalamic secretion of corticotropin-releasing factor (CRF), a 41 amino-acid peptide21, 22. CRF is heterogeneously distributed in the CNS, where it serves to orchestrate the endocrine (HPA axis), autonomic, immune and behavioral responses to stress. CRF neural pathways extensively interact with serotonergic and noradrenergic circuits. The behavioral effects of administered CRF in laboratory animals are strikingly similar to the symptoms of major depression. CRF is hypersecreted in some depressed patients, which led us and others to suggest that CRF receptor antagonists might act as antidepressants. There are two major CRF receptor subtypes, and several pharmaceutical companies are actively testing CRF1 receptor antagonists as antidepressants. In a variety of preclinical models, CRF1 receptor antagonists possess antidepressant properties. Janssen Pharmaceuticals halted development of R121919, a potent CRF1 receptor antagonist, because of hepatotoxicity, apparently unrelated to blockade of the CRF receptor. Nevertheless, early open clinical trials provided evidence of antidepressant efficacy23. A number of promising CRF1 receptor antagonists are currently under study.

Although most investigators believe that hypercortisolemia is a consequence of CRF hypersecretion associated with depression, the marked hypercortisolemia observed in psychotic depression, a subtype of depressives characterized by delusions and/or hallucinations, has led to impressive studies indicating that the glucocorticoid receptor antagonist mifepristone (RU486) is very effective in the treatment of psychotic depression24. Large-scale, double-blind, randomized clinical trials are currently being conducted by Corcept in the United States.

The neurokinin1 (NK1) receptor is a tachykinin receptor for the endogenous neuropeptide transmitter substance P. NK1 antagonists were originally scrutinized for analgesic properties without success. However, an NK1 antagonist MK-869 (Merck) exhibited efficacy in a placebo-controlled clinical trial for depression, comparable to the active comparator paroxetine25. The finding of efficacy in this study has led other pharmaceutical companies to develop NK1 antagonist programs26.

There has been significant progress in the design and testing of radioligands for in-vivo positron emission tomography (PET) imaging in humans to identify pathophysiological subtypes of mood disorders and thus predict appropriate treatment(s) for patients. Serial imaging of the density of cell surface receptors and transporters in individuals will undoubtedly provide invaluable information concerning the biology of mood disorders. More immediate will be the use of such techniques to optimize drug choice and dosing. With PET or SPECT ligands now available for the DA and 5-HT transporters, and development of ligands for the NE transporter in progress, it will be of great interest to follow transporter occupancy as a function of antidepressant dose to determine if this measure correlates with antidepressant efficacy. Until recently, there has been surprisingly sparse information on the magnitude of transporter occupancy during antidepressant treatment. Approximately 80% of 5-HT transporter is occupied by standard doses of two SSRIs, paroxetine and citalopram27. It is not known what level of transporter occupancy is necessary for producing functional changes in neurotransmitter concentrations or whether small increments of blockade of NE or DA transporters, in the presence of considerable 5-HT transporter blockade, may provide additional clinical benefit.

Future directions
Finally, we suggest several exciting areas of research that plausibly might lead to new treatments. Neurogenesis occurs in the adult hippocampus, glucocorticoids decrease neurogenesis, and both serotonergic and noradrenergic antidepressants, as well as ECT, increase neurogenesis. The link among the hippocampus, glucocorticoids, monoamine systems and mood disorders seems clear, although their exact mechanisms of interaction remain obscure. In addition, some agents used in the treatment of bipolar disorder modify apoptotic pathways; for instance, valproic acid increases expression of the protective protein bcl-2. In addition, chaperone proteins are important in regulating steroid receptor translocation, and other proteins are involved in trafficking of cell surface receptors and transporters over short (seconds to minutes) time spans. Thus, medications altering the function of these proteins may also modify neurotransmission. Should problems with delivery to the brain be overcome, antisense technology could be used in the treatment of psychiatric disorders as it has been for cystic fibrosis and cancer. Collectively, these approaches could conceivably represent new targets for mood disorder treatments.

Received 1 July 2002; Accepted 4 September 2002; Published online 28 October 2002.




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