Although many of the currently available antidepressants are safe and effective, the search for novel treatments with improved efficacy and a more favorable side-effect profile continues. This article focuses on novel classes of putative antidepressant drugs and other somatic treatments that show promising evidence of antidepressant properties in either preclinical and/or clinical studies. In addition, several paradigms for detecting antidepressant activity will be discussed.

The currently available antidepressants can be classified as belonging to one of several major classes: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), combined serotonin/norepinephrine reuptake inhibitors (SNRIs), 5HT₃ antagonists, and alpha₂/5HT₂/5HT₃ antagonists. The latter group, exemplified by mirtazapine, has a unique pharmacologic profile. It appears to increase both serotonin (5HT) and norepinephrine (NE) neurotransmission and might exhibit a faster onset of action than the other drugs available.^[1-3] One of the major problems with SSRIs, SNRIs, and NRIs, the most widely used antidepressants currently available, is the relatively long lag time before clinical efficacy is observed in most patients. Newer drugs might provide faster-acting antidepressants, thereby improving both patient outcome and adherence to treatment. Furthermore, drugs that target neurotransmitter systems other than NE and 5HT may be very useful either as novel monotherapy or as adjuncts to our current pharmacopoeia.

*This summary mentions off-label uses for some medications. These may describe clinical uses for medications that have not been approved by the US Food and Drug Administration.

Many drugs act by binding to neurotransmitter or transporter (uptake site) receptors located in the central nervous system (CNS) or periphery. The potency of a drug (the concentration needed to produce an effect) is directly related to its affinity to its target receptor. Ideally, a drug possesses a high affinity and is highly selective for its target receptor (ie, has negligible binding at other receptors). As such, most currently available drugs specifically target 5HT and/or NE system receptors or transporters, as these two neurotransmitter systems have been the major focus of current strategies to treat depression. The specificity of a compound is of considerable importance because binding at certain receptors, such as the muscarinic cholinergic, alpha-1 adrenergic receptor, or histamine H₁, can lead to a variety of troubling side effects (eg, dry mouth, constipation, nausea, orthostatic hypotension, and nausea).

Escitalopram (Lexipro) has recently received US Food and Drug Administration (FDA) approval for the treatment of depression in the United States. Escitalopram is S-citalopram, the active enantiomer of the SSRI citalopram (Celexa), a racemic mixture of the R- and S-enantiomers, an antidepressant available for the last several years. The development and efficacy of escitalopram is of particular interest because it highlights the principle that one particular stereoisomer of a molecule may possess greater clinical efficacy than another.

Stereoisomerism refers to 2 molecules with the same basic molecular framework differing only in the spatial arrangement of the atoms. This is analogous to the left and right hand, which contain the same "parts" (ie, 4 fingers and a thumb), but are actually nonsuperimposable mirror images of each other. As noted above, citalopram is a mixture of the 2 isomers S-citalopram and R-citalopram. However, in vitro data have demonstrated that the S-isomer of citalopram binds with far greater potency to the 5HT transporter than does its R-counterpart (analogous to the left hand fitting much more snugly into a left-handed glove).^[4]

Escitalopram's pharmacologic profile is impressive: it is a remarkable SSRI^[4] and is more potent than citalopram in both in vitro and in vivo studies. It also lacks affinity for postsynaptic receptors that contribute to side effects of other psychotropic drugs. The pharmacokinetics of escitalopram are comparable to citalopram, including a slightly shorter half-life (27-32 hours) and less protein binding (56% compared with 80% with citalopram). Like citalopram, escitalopram is active in animal models of both depression and anxiety.^[5]

Clinical studies have been consistent with the in vitro profile of the compound. In a fixed-dose study, escitalopram treatment produced a robust decrease in all depression severity, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) and the 24-item Hamilton Rating Scale for Depression (HAM-D), at half the dose required to obtain similar results with citalopram (10-20 mg/day for escitalopram vs 40 mg/day with citalopram).^[6] Another study indicated that patients treated with escitalopram at 10 mg/day showed significant improvement relative to placebo.^[7] There is also some indication that escitalopram may have a more rapid onset of action than citalopram. In a recent study, escitalopram was significantly more efficacious than placebo after only 1 week of treatment.^[5]

Although not FDA approved in the United States, reboxetine is a relatively new antidepressant that is a potent and selective NRI. It has negligible affinity for noradrenergic alpha₁ or alpha ₂ receptors, histaminergic H₁ receptors, dopaminergic D₂ receptors, or muscarinic cholinergic receptors, indicating a low probability of side effects.^[8] In addition, it has linear pharmacokinetics, no active metabolite, and is eliminated principally via renal mechanisms.^[9] Because of its increase in sympathetic nervous system tone, reboxetine increases the frequency of urinary hesitancy. While studies indicate that reboxetine is the only highly selective NRI and its efficacy is accepted in many countries, several recent studies in the United States have produced negative results, and it is currently not approved for use in the United States.

SSRIs have become the dominant treatment for depression in the United States, predominantly due to their favorable side effect profile compared with TCAs. However, recent evidence indicates that less selective compounds may have greater efficacy than the SSRIs, specifically compounds that block both 5HT and NE reuptake. Currently available "dual reuptake inhibitors," or SNRIs, include milnacipram, venlafaxine, and duloxetine, as well as many of the older-generation tricyclic antidepressants. Duloxetine, which shows high affinity for both the 5HT transporters (SERTs) and NE transporters, has shown consistent clinical efficacy in 5 of 6 placebo-controlled studies with doses between 60 and 120 mg/day.^[10] A long-term open-label safety study is under way looking at doses of 80-120 mg/day over 1 year. Overall, duloxetine is an efficacious drug with a good side-effect profile and has recently been approved by the FDA for the treatment of depression.

Several other compounds have been tested in controlled clinical trials and demonstrated little or no efficacy. Igmesine, developed by Parke-Davis, now a division of Pfizer, a putative sigma opioid receptor antagonist, has failed phase 2 clinical trials. Flesinoxan, a 5HT_1A agonist developed by Solvay, has been removed from clinical development due to several failed clinical trials in the United States. Gepirone, another 5HT_1A agonist currently being developed by Organon, is still in phase 2 and phase 3 trials; some recent studies using higher doses and a sustained-release formulation have suggested efficacy in depression. A selegiline patch, manufactured by Somerset Pharmaceuticals, is also available. Selegiline is a monoamine oxidase B inhibitor and is currently marketed for use in Parkinson's disease. Drug delivery via a patch avoids some of the gastrointestinal side effects associated with selegiline use, and also results in CNS monoamine oxidase A inhibition. Clinical trials with this patch in depression have been positive, and the company is awaiting an FDA review.

The evidence for corticotropin-releasing factor (CRF) hypersecretion in depression and certain anxiety disorders is compelling. A plethora of evidence, some dating back more than 100 years, has demonstrated that dysfunction of the hypothalamic-pituitary-adrenal (HPA axis) may lead to specific psychiatric disturbances, exemplified by the frequent demonstration of hypercortisolemia in depressed patients. Numerous studies have demonstrated abnormalities in HPA axis activity in glucocorticoid function in depressed patients, including elevated plasma and cerebrospinal fluid (CSF) cortisol concentrations in depressed patients,^[11,12] increased 24-hour urinary free cortisol concentrations, and increased levels of cortisol metabolites in urine.^[13]

At the pinnacle of the HPA axis is CRF, also known as corticotropin-releasing hormone (CRH), a 41 amino acid peptide that is released from the hypothalamus during stress. CRF is transported to the anterior pituitary via the hypothalamo-hypophyseal portal system where it promotes the release of adrenocorticotropic hormone (ACTH) into the general circulation, which in turn stimulates the production and release of cortisol from the adrenal cortex. It is now evident that CRF modulates not only the endocrine responses to stress, but the autonomic, immunologic, and behavioral responses as well.^[14,15]

Numerous studies have revealed that the direct injection of CRF into the CNS of laboratory animals produces effects reminiscent of the cardinal symptoms of depression, including decreased libido, reduced appetite and weight loss, sleep disturbances, and neophobia. Two CRF receptor subtypes, CRF₁ and CRF₂, have been identified and shown to exhibit distinct anatomic localization and receptor pharmacology.^[16] The CRF₁ receptor is predominantly expressed in the pituitary, cerebellum, and neocortex in the rat. A growing body of evidence from animal studies has shown that the CRF₁ receptors may be the prime mediator of some of the anxiogenic-like behaviors observed after administration of CRF.^[17,18] The CRF₂ receptor family is composed of 2 primary splice variants, CRF_2A and CRF_2B. The CRF_2A receptor is more prevalent in subcortical regions, such as the ventromedial hypothalamus, lateral septum, and dorsal raphé nucleus (DR), whereas CRF_2B is more abundantly expressed in the periphery. In addition to CRF, several other endogenous peptide ligands for CRF receptors have recently been discovered, including urocortin,^[19] urocortin II, urocortin III, and perhaps others.^[20] As is often the case, the discovery of several new putative endogenous ligands has raised many new questions in the field, particularly regarding the pharmacology and functional interactions between these ligands and their receptors.

Outside of its classical role as a secretagogue for ACTH, and perhaps of even greater relevance to psychiatric disorders, is the proposed function of CRF in circuits other than the HPA axis. Indeed, results from both clinical studies and a burgeoning database derived primarily in rodents and lower primates have indicated the importance of extrahypothalamic CRF circuits.^[14,17] In rodents, primates, and humans, CRF and its receptors have been heterogeneously localized in a variety of regions, including the amygdala, thalamus, hippocampus, prefrontal cortex, and others.^[21-24] These brain regions are known to be important in regulating many aspects of the mammalian stress response, and in regulating affect. The presence of CRF receptors in both the DR and locus coeruleus (LC), the major serotonergic and noradrenergic cell body-containing regions in the brain, respectively, also deserves comment. Because most available antidepressants, including the TCAs and SSRIs, are believed to primarily act via modulation of noradrenergic and/or serotonergic systems, the neuroanatomic proximity of CRF and monoaminergic systems provides a plausible site for interaction between CRF systems and antidepressants.

Involvement of extrahypothalamic CRF systems in the pathophysiology of depression is suggested by numerous studies showing elevated CRF concentrations in the CSF of drug-free depressed patients,^[25,26] though a discrepant report has appeared.^[27] A reduction in concentrations of CRF in CSF has been observed in healthy volunteers treated with the tricyclic antidepressant desipramine^[28] and in depressed patients following treatment with fluoxetine^[29] or amitryptiline,^[30] providing further evidence of a possible connection among antidepressants, noradrenergic neurons, and CRF systems. Similar effects have been reported after electroconvulsive therapy in depressed patients.^[31]

Based on this CRF hypothesis of depression, newly developed CRF₁ receptor antagonists represent a novel putative class of antidepressants. Such compounds show activity in a wide array of preclinical screens for antidepressants and anxiolytics. Recently, a small open-label, phase 1 safety study evaluated the efficacy of R121919, a CRF₁ receptor antagonist, in major depression.^[32] Standard severity measures of both anxiety and depression were reduced after R121919 treatment. Although this drug is no longer in clinical development, it is clear that CRF₁ antagonists represent a potentially new class of psychotherapeutic agents to treat anxiety and affective disorders. Other compounds are currently being developed by Bristol-Myers Squibb, Novartis, Pfizer, and Neurogen, among others, and are in various stages of preclinical and clinical development. While it is clear that additional research needs to be conducted, CRF receptor antagonists show promise as a novel treatment strategy for depression.

Mifepristone (also known as C-1073 or RU-486) is a potent glucocorticoid (GR II) and progesterone receptor antagonist, with no effects on the mineralocorticoid receptor in vivo. The GR II receptor is located throughout the brain, with high expression in the frontal cortex and hippocampus. Several recent studies have suggested blockade of the GR II may be a novel treatment strategy for major depression with psychotic features, as elevated cortisol levels are particularly common in this depression subtype.

A small, double-blind, placebo-controlled study was recently completed with 5 subjects, 3 men and 2 women. In this crossover study, patients received 4 days of placebo followed by 600 mg mifepristone, or vice versa with no washout period. Outcome measures were standard rating scales including the HAM-D and Brief Psychiatric Rating Scale (BPRS). During the mifepristone phase, there was a 34% decrease in the BPRS score; BPRS scores increased by 1% during the placebo phase. The HAM-D scores declined by 26% during the mifepristone phase vs 6% during the placebo phase. This study clearly suggested disruption of glucocorticoid receptor signaling may result in an improvement in psychiatric symptoms.

A larger multicenter study has also been completed in which patients with psychotic major depression received 50 mg, 600 mg, or 1200 mg per day of mifepristone for 7 days; this study was not double-blinded,^[33,34] but demonstrated that mifepristone caused a rapid reduction in symptoms, with a greater response to treatment with increased dosage. These studies are very promising as they suggest the possibility of a rapid and effective treatment for psychotic depression; we await the results of ongoing phase 2 and phase 3 clinical trials.

Mirtazapine is a relatively new antidepressant that is referred to as a NaSSA, or noradrenergic and specific serotonergic antidepressant. Mirtazapine is a potent alpha₂ receptor antagonist with no effect on monoamine reuptake; however, in vitro microdialysis has demonstrated that mirtazapine increases both noradrenergic and serotonergic transmission.^[35] Mirtazapine also acts as an antagonist at both the 5HT₂ and 5HT₃ receptors. The 5HT₂ receptor blockade is believed to contribute to both the anxiolytic effects and benefits on sleep.^[36] Mirtazapine also appears to have a much lower incidence of sexual dysfunction relative to the SSRIs.^[36] A double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients has recently been completed. This study demonstrated greater efficacy and greater tolerability of mirtazapine relative to paroxetine, although both had significant antidepressant activity. The mirtazapine-treated patients also showed more pronounced antidepressant effects in the first weeks of treatment, suggesting mirtazapine has an earlier onset of action. Several other studies have also suggested that mirtazapine may have a more rapid onset of antidepressant action than SSRIs (fluoxetine, paroxetine, and citalopram).^[37] As post-hoc analysis can be problematic, these findings await confirmation from specifically designed prospective onset of action studies.

SP and other neurokinins are involved in pain and inflammation pathways, and perhaps in the regulation of emotion. SP antagonists have recently generated interest as potential antidepressants. Mammalian members of the tachykinin family are known as neurokinins^[38] and include neurokinin A, neurokinin B, and SP. The most well known and abundant of the neurokinins, the undecapeptide SP binds to the neurokinin 1 (NK-1) receptor, neurokinin A (NKA) to the neurokinin 2 (NK-2) receptor, and neurokinin B (NKB), to the neurokinin 3 (NK-3) receptor. Within the CNS, SP is localized within limbic, hypothalamic, and brainstem areas (amygdala, hypothalamus, periaqueductal gray, LC, and parabrachial nucleus)^[39] and is colocalized in NE- and 5HT-containing cell bodies as well.^[40-43] Furthermore, SP and other tachykinins serve as pain neurotransmitters in primary afferent neurons,^[44] and mediate a variety of other peripheral actions, including bronchoconstriction, vasodilatation, salivation, and smooth muscle contraction in the gut.^[45,46]

Preclinical studies have provided much of the impetus to continue investigation of the potential efficacy of SP receptor antagonism in psychiatric disorders, particularly when these agents have not been effective as analgesics.^[47] SP (or SP agonist) administration to animals elicits behavioral and cardiovascular effects resembling the stress response and the so-called "defense reaction."^[48] Moreover, preclinical studies document a reduction of behavioral and cardiovascular stress responses by administration of SP receptor antagonists.^[49,50] A breakthrough study indicated that the SP receptor antagonist MK-869 was more effective than placebo, had no sexual side effects, and was as effective as paroxetine in patients with major depression with moderate to severe symptom severity.^[50] A second follow-up study was unsuccessful, but another Merck NK1 antagonist also showed efficacy in major depression. MK-869 is still under active study for both depression and anxiety disorders.

Future clinical investigations will determine whether brain and CSF SP concentrations are altered in patients with major depression, as the extant data are inconclusive,^[51,52] and whether there are significant changes in CSF SP concentrations after treatment.^[53] Moreover, we await the results of several ongoing studies of SP antagonists in mood and anxiety disorders.^[54] A role for SP in the pathophysiology of asthma, irritable bowel syndrome, and migraine is also under investigation.

Vagal Nerve Stimulation

Vagus nerve stimulation (VNS), approved in 1997 as a treatment for refractory epilepsy, may also exert antidepressant properties. The procedure involves implantation of a small pulse generator under the skin on the upper left side of the chest. Electrodes connect the generator to the left vagus nerve, thereby sending regular pulses of electrical energy into the brain via the vagus nerve.^[55] The side-effect profile for VNS is relatively mild and tends to diminish with time; common side effects are cough, hoarseness, voice alteration, and paresthesias.^[56] Connectivity between the vagal nerve afferents and the limbic system, as well as other brain regions important in the modulation of affect, suggest the potential clinical efficacy of VNS in the treatment of depression.

Positron emission tomography (PET) studies show changes in critical areas during VNS.^[57] An open pilot study performed by Sackeim and colleagues on 60 patients with treatment-resistant major depression showed a response rate of 30.5% for the primary HRSD(28) measure, 34.0% for the MADRS, and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2).^[58] Better response rates were seen in patients with low to moderate antidepressant resistance than in extremely treatment-resistant patients (those who had previously failed more than 7 adequate antidepressant trials). Long-term therapeutic data are still necessary to determine what role, if any, VNS will play in treatment-resistant depression.

Transcranial Magnetic Stimulation (TMS)

Another alternative approach to the treatment of depression is the use of TMS. TMS is performed by placing an electromagnetic coil on the scalp through which high-intensity current is rapidly turned on and off, resulting in a magnetic field. Current flow in neural tissue is generated due to the proximity of the magnetic field. A potential region of action for TMS is the dorsolateral prefrontal cortex (DLPFC), which is situated in the lateral aspect of the middle frontal gyrus and is accessible to current generated by the TMS coil.^[59] Early studies showed mood modulation with TMS; left DLPFC stimulation caused transient sadness whereas right DLPFC stimulation led to transient happiness. Many studies have been performed, both open and blinded sham-controlled trials, suggesting efficacy in treating depression,^[56,59-63] but negative results have also been reported.^[64] A comprehensive review of the extant literature indicates that the evidence that this is effective in the treatment of depression remains unconvincing.^[65]

Drug development in psychiatry is impeded by gaps in our understanding of both the underlying pathophysiology of the disorders and the exact mechanisms by which pharmacologic agents target these disorders. Little is known about adaptive responses that the brain undergoes during the course of disease or its treatment. The pharmacokinetics and pharmacodynamics of various psychotropic medications have not been completely elucidated. Brain penetrance, accumulation, and elimination of drug are poorly understood, and without definitive knowledge of the dose- and time-effect relationships for drug molecular targets, it is difficult to determine the efficacy of novel drugs.

Brain imaging may have a potentially great impact on many areas of psychiatric medication development. It could facilitate everything from testing molecular sites of action for novel agents to quantifying substrates of treatment efficacy in patients (eg, receptor occupancy). Functional brain imaging methods might also be used to identify the effective dose range prior to clinical trials, thereby optimizing positive outcomes. Additionally, imaging techniques might be useful in helping define the basis of treatment nonresponse.

Clinicians and scientists have exploited technology to enable neuroimaging of several different functional modalities: electroencephalogram maps bioelectric activity; magnetoencephalography maps biomagnetic activity; functional magnetic resonance imaging, PET, and single photon emission computed tomography (SPECT) measure regional cerebral blood flow and metabolic rate, the latter 2 transporter and receptor occupancy as well; and magnetic resonance spectroscopy is able to demonstrate in vivo pharmacokinetics as well as markers of glial and neural integrity. Via these many and varied modalities, in vivo brain imaging has the potential to solve many questions in depression research. Does administration of an SSRI result in the dose-dependent occupancy of in situ brain SERTs? Do specific delayed changes in distributed brain activity emerge with prolonged SSRI administration? Do such changes relate to treatment response and nonresponse? Are such changes common in response to active treatment and placebo effect?

In Vivo Determination of Drug Actions With PET

One emerging technology in the field uses PET imaging to define the in vivo interaction of drugs with their target receptor. A radioactively labeled compound is injected intravenously and PET neuroreceptor imaging is performed to determine radioligand binding in different brain regions. A recent study highlights the use of such ligands in defining the in vivo interaction of SSRIs with brain SERTs.^[66] Occupancy of the human brain SERT by orally administered SSRIs was determined by observing decreased binding of ^[11C]DASB (a radioligand that binds the SERT) after treatment with paroxetine or citalopram, 2 SSRIs. The study shows a close correlation between striatal SERT occupancy and serum paroxetine levels.

Currently, work is being conducted in nonhuman primates to develop more specific radioligands for the SERT. In a recent unpublished study (C. Kilts, personal communication, July 2002), potent in vivo occupancy of SERT by S-citalopram was demonstrated in nonhuman primates at doses as low as 0.1 mg/kg; in comparison, R-citalopram was very weak. This study highlights the use of brain imaging in the identification of comparative clinical efficacy for different drugs, as other studies have shown that S-citalopram is the clinically active component of citalopram.

A seminal study by Mayberg and colleagues^[67] is worth noting. They used PET in hospitalized unipolar depressed patients to assess the effects of fluoxetine. Responders and nonresponders to fluoxetine showed different patterns of functional brain activity at 6 weeks. Clinical improvement was associated with decreased blood flow in limbic and striatal regions and increased activity in brain stem and dorsal cortical regions. Nonresponders to drug treatment showed the same pattern at 1 and 6 weeks and lacked either subgenual, cingulate, or prefrontal changes. The appearance of a different brain activation pattern in drug responders at 6 weeks as compared with 1 week indicates a process of adaptation in specific brain regions over time in response to chronic drug administration. These results suggest that treatment nonresponse is correlated with a failure to induce these adaptive changes and indicate that functional brain imaging can be a pivotal technique in identifying nonresponding patients. Such a methodology could allow clinicians to know more quickly which patients are not adapting to a certain medication and allow a more timely switch to a more appropriate therapeutic strategy, thereby shortening the duration of clinical morbidity for the patient.

The future for the treatment of depression is promising and directed toward both improving diagnosis and developing more rapid and effective therapeutics. Several new modalities are entering into phases of testing to determine whether they will be clinically useful, including diagnostic techniques such as PET and SPECT, and pharmacologic interventions including the newer SNRIs and CRF₁ receptor antagonists. Much of the current research indeed seeks to move beyond the 5HT and NE systems and identify and target other components in the pathophysiology of depression such as SP and CRF. As our understanding of the underlying neurobiology of the disease grows, so will our ability to provide patients with effective interventions that provide relief from the debilitating symptoms of depressive illness with fewer side effects.

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