Etiology and Pathophysiology
Minor depression is only a proposed diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and there are no International Classification of Diseases codes to categorize it. The proposed diagnostic category for minor depression in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition describes a depressive disorder that requires the presence of two to four symptoms of depression, lasting for at least two weeks, that are identical to major depressive episodes in duration but involve fewer symptoms and less impairment.
Whether this proposed category will become an official category is unclear. After careful empirical review and commentary from experts in the field of psychiatry, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Task Force and Work Groups determined there was insufficient information to warrant inclusion of minor depression as an official category in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. DSM-III includes a chronic form of minor depression — dysthymia — as a diagnostic category, but minor depression lasting less than two years is considered part of the atypical depression category.
Investigators have used a variety of definitions and analytic strategies to determine the definition and impact of minor depression. Researchers have decided that minor depression causes functional impairment and is correlated with developing major depression and that patients can alternate between major and minor depression. A large, multicenter study involving 162 participants defined minor depression as at least two weeks of depressed mood (including dysphoria, sadness, or anhedonia), a score of 70 or less on the global assessment of function scale, and a score of 75 or less on the social role function scale.
This study observed patients for four weeks during a placebo lead-in period, followed by a comparative study for different therapies. The conclusions from the placebo lead-in trial were that minor depression is not a focal event but a chronic persistent disease characterized by mood and cognitive symptoms that can be independent of or linked to developing major depression, with a continuum of severity. Much like major depression, minor depression is a potentially lucrative market for drug developers because of its prevalence, the functional and cognitive disability associated with the disorder, its recurrent nature, and the shortcomings of the numerous antidepressant agents that have reached the market.
Although drug classes such as the selective serotonin reuptake inhibitors and the serotonin/norepinephrine reuptake inhibitors have proved both effective and well tolerated in many depressed patients, new agents are needed to target more mechanisms that may be involved in the initial cascade of events that trigger a depressive episode or that can deliver efficacy without the troublesome side effects of currently available drugs (namely, sexual dysfunction). The following section discusses the etiology of the disease and factors that investigators believe may predispose people to depression.
It also discusses researchers’ current understanding of the pathophysiological processes involved in depression and highlights some potential new drug targets for novel antidepressant therapies. To date, there is not substantial research to support describing the difference in etiology among the various severity forms of depression; therefore, the discussion here focuses on the mechanisms implicated in depressive disorders in general and in major depression in particular, for which there is more published research.
Etiology
The onset of depression is believed to result from a combination of genetic and environmental factors, and the medical literature is replete with findings to support this view. Like other diseases of multifactorial causation (such as heart disease, which is related to smoking, blood pressure, obesity, and other factors), depression appears to occur when several factors combine to trigger the condition. Although a familial link has been well established by studies showing that people who have a family history of depression are at a higher risk for developing the condition than people who have no family history, the question of whether the underlying cause of the familial link is more a result of shared genetics or a shared environment remains unanswered.
The reasons for differences in levels of inherited predisposition to depression in different people are unclear, but mounting evidence suggests that specific aspects of the environment — that is, stressful life events or ongoing, severe social stress and lack of social support — trigger the condition in people who are genetically predisposed. In support of this theory, investigators have presented evidence suggesting a role for the serotonin transporter (5-HTT) gene in the interaction with environmental stressors; this finding could provide insight into the gene-environment interaction that leads to depression.
A 25-year prospective-longitudinal study followed more than 1,000 people in New Zealand from birth. Investigators found that people carrying the short (“s”) allele in the 5-HTT gene-linked polymorphic region (5-HTTPLR) whose “life events” (i.e., recorded stressful experiences) occurred after age 21 experienced increases in depressive symptoms from age 21 to age 26; people with the long (“1″) allele did not experience such increases. More-detailed analyses from this study revealed that the 5-HTT gene interacts with life events to predict not only depression symptoms and increases in these symptoms but also depression diagnoses, new-onset diagnoses, suicidality, and informants’ reports of depressed behavior.
The findings of the New Zealand study strongly support the gene/environment interaction hypothesis as a cause of depression. Rather than holding genes (and gene interactions) wholly responsible for depression, the authors propose a more “evolutionary” model; they view stressful life events in the same light as environmental pathogens and argue that the effects of genes may be uncovered when “such pathogens are measured (in naturalistic studies) or manipulated (in experimental studies).” Overall, this shift in investigators’ approach to research in psychiatric genetics may improve their understanding of the complex interactions between genes and the environment that take place in poorly understood conditions like depression and ultimately uncover other genes that may be critical in triggering the disease.
Pathophysiology
Because depression is a very heterogeneous disorder, researchers suspect that no one pathway leads to depression in all patients. Several neuromodulators appear to play important roles in the cascade of events leading to depression. Neuroimaging studies have identified structural abnormalities and/or volume loss in several brain regions (e.g., cortical regions, hippocampus, nucleus accumbens, amygdala, certain hypothalamic nuclei) in depressed patients. Interestingly, studies suggest that antidepressant medications — which regulate neuromodulators such as serotonin, norepinephrine, and substance P — might protect depressed patients from hippocampal loss.
The following section discusses researchers’ current understanding of the roles of several neuromodulators in the pathophysiological cascade of events leading to depression.
Monoamine Hypothesis
Although researchers do not completely understand the mechanisms that cause depressive symptoms, they widely acknowledge the pathophysiology of depression is linked to brain neurochemistry. The long-held “monoamine hypothesis” implicates a deficiency of central noradren-ergic and/or serotonergic systems. In support of the theory, antidepressant drugs that increase monoamine concentrations have been shown to relieve symptoms of depression. The neurotransmitters that appear to be strongly associated with depression are the monoamines serotonin (5-HT), norepinephrine, and dopamine. Evidence supporting a role for these neurotransmitters in depression derives primarily from the study of antidepressant drugs that act on these neurotransmitter systems.
Researchers, however, have never proved that the symptoms of depression are caused by a deficiency in certain neurotransmitters. Indeed, the monoamine-depletion theory of depression is not compatible with the realities of clinical practice: specifically, antidepressant drugs that raise monoamine concentrations do so quickly, within hours or days, while depressive symptoms persist for weeks before patients experience the drugs’ therapeutic effect. This paradox can be explained by the downregulation of 5-HT receptors in long-term selective serotonin reuptake inhibitor treatment: the decline in 5-HT receptors leads to desensitization of the 5-HT pathway. This effect is consistent with the two- to three-week lag in selective serotonin reuptake inhibitor efficacy in treating depression.
Another hypothesis explaining the delay in response to antidepressant treatment is that depression involves a malfunction in neurons’ response to rnonoamines, not a deficit in rnonoamines. Antidepressant therapy may work by remedying this malfunction after a delay of several weeks. Researchers theorize that symptoms of depression result from poor uptake of rnonoamines by postsynaptic transporters. The leftover rnonoamines are reabsorbed by the presynaptic cell; consequently, the presynaptic cell releases fewer rnonoamines into the synaptic cleft. The net result is a monoamine deficit in the synaptic cleft. Most antidepressant drugs work by blocking the reuptake of rnonoamines by presynaptic cells.
Some researchers believe that cellular autoreceptors cause the delay in treatment effect. These autoreceptors function to maintain a healthy balance of neurotransmitters in the synaptic cleft. As mentioned, treatment with antidepressants blocks reuptake of rnonoamines by the presynaptic cell, which therefore releases more rnonoamines into the synaptic cleft. Autoreceptors react to the initial flood of neurotransmitters by halting the production and release of rnonoamines from the presynaptic cell. After a few weeks of treatment, the autoreceptors stop reacting to the excess rnonoamines, allowing the presynaptic cell to return to producing and releasing the surplus neurotransmitters into the cleft. Despite the debate surrounding the validity of the monoamine hypothesis, monoamine-based therapies continue to be developed.
Other possible neurotransmitters are also under research for depression, and several emerging therapies target more than one transmitter (e.g., Eli Lilly’s duloxetine, Merck’s DOV-216303, GlaxoSmithKline’s NS-2359). The next sections discuss in detail three neurotransmitters and their roles in drug development. Substance P antagonists are also covered here because recent studies indicate that these compounds regulate monoamine activity in the brain.
Serotonin
Interest in 5-HT as a target of antidepressant action was first proposed in the 1960s; researchers hypothesized that low concentrations of this monoamine causes depression, a theory inspired by the observation that depressive symptoms occur as a side effect of certain antihypertensive drugs that work by depleting reserves of catecholamines — e.g., reserpine. Additional recent data further linking serotonin and depression support this theory; researchers have found that suicidal depression (specifically in patients classified as impulsive) is linked with low cerebrospinal fluid and plasma levels of 5-hydroxy-indoleacetic acid (5-HIАА), a 5-HT metabolite produced when serotonin is destroyed by monoamine oxidase. Discovery of reduced levels of the metabolite in people with suicidal depression suggests that a serotonin deficit may contribute to suicidal depression.
At least 15 subtypes of the 5-HT receptor have been classified according to their pharmacology and function; the 5-HT1 and 5-HT2 receptor subtypes have received the most attention in depression research. 5-HT agonists such as Otsuka/Vela’s sigma receptor/5-HT1A agonist OPC-14523 (Phase II trials for depression in the United States); Mitsubishi-Tokyo’s 5-HT1a agonist MKC-242 (Phase II trials in Europe and Japan); and Servier’s 5-HT1a agonist alnespirone (Phase II trials in Europe) are all in development for depression.
Other 5-HT antagonists in development for this indication are AstraZeneca’s AR-A2, a 5-HT 1B receptor antagonist in Phase II development for anxiety and depression; Pfizer’s 5-HTib/id antagonist elzasonan and Solvay’s 5-HT1a antagonist DU-125530, both in Phase II development; and Servier’s agomelatine, а 5-НТ2A, 5-HT2C antagonist/melatonin agonist in Phase III development. However, the selective serotonin reuptake inhibitors that first launched in the 1980s have most successfully validated the theory of serotonin’s role in depression.
Selective serotonin reuptake inhibitors act by selectively inhibiting the presynaptic reuptake of serotonin while exerting little effect on norepinephrine and dopamine uptake. After a serotonergic neuron fires, 5-HT is normally transported back into the presynaptic neuron for repackaging and subsequent re-release. Selective serotonin reuptake inhibitors block the reuptake mechanism and consequently increase the level of 5-HT in the synaptic space surrounding the neuron.
The excess 5-HT activates all 5-HT receptors, both pre- and postsynaptically. The activation of the anxiogenic postsynaptic 5-HT2A receptors by selective serotonin reuptake inhibitors may explain the initial increase in anxiety that selective serotonin reuptake inhibitors cause in some patients, as well as the sexual side effects associated with this class of drugs. Citalopram and escitalopram show the greatest selectivity for serotonin over norepinephrine, followed by sertraline, paroxetine, fluvoxamine, and fluoxetine, in that order.
Norepinephrine
Ever since the introduction of Eli Lilly’ s fluoxetine (Prozac) — the first selective serotonin reuptake inhibitor to be marketed for depression — antidepressant drug development has concentrated largely on blocking 5-HT reuptake. However, multiple neurotrans-mitters appear to be associated with depression. Since the 1960s, when tricyclic antidepressants were becoming popular, and later in 1997, with the introduction of venlafaxine, a serotonin/norepinephrine reuptake inhibitor (serotonin/norepinephrine reuptake inhibitor), investigators have been interested in the roles of norepinephrine in depression.
Duloxetine (Eli Lilly’s Cymbalta) is the most recently launched serotonin/norepinephrine reuptake inhibitor and is considered to have a more balanced effect on serotonin and norepinephrine when compared with venlafaxine. The therapeutic success of drugs that act on the norepinephrine neurotransmitter system or on serotonin systems concurrently confirms that the cascade of events leading to depression involves multiple neurotransmitter systems. Researchers are striving to ascertain the trigger and path of this cascade.
Dysregulation of norepinephrine signaling alone may precipitate or accentuate depression. This theory suggests that drugs that act as adrenergic agonists may be potent antidepressants. Adrenergic neurons are found mainly in the locus coeruleus in the brain stem. These neurons project into many areas of the brain and spinal cord, including the prefrontal cortex, which controls drive and motivation. Areas of the brain that receive inputs from adrenergic neurons contain adrenergic receptors. Adrenergic receptors are divided into the alpha and beta subtypes and further classified by their affinity for different agonists and antagonists. Sanofi-Aventis’s SR-58611, which entered Phase III trials in September 2003, is an example of a highly selective agonist for beta-3-adrenoreceptors. This agent is under investigation for the treatment of major depression because it acts indirectly as a noradrenergic agent, preventing the reuptake of norepinephrine.
Dopamine
Many emerging therapies focus on the manipulation of dopamine signaling, either in combination with just norepinephrine (e.g., GlaxoSmithK-line’s radafaxine) or in combination with both norepinephrine and serotonin (triple-reuptake inhibitors [e.g., DOV-216303]). Malfunctioning of dopamine in the brain is thought to cause anhedonia, an inability to experience pleasure and a symptom of depression. Plasma concentrations of a dopamine metabolite, homovanillic acid, are reduced in patients with depression. Chronic treatment with antidepressants can lead to sensitization of dopamine receptors, which appears to be important for treatment efficiency.
The primary efficacy of selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors may not be due to changes in serotonin and norepinephrine signaling but instead to reactive changes in dopamine signaling. Selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors may act to alter the level of dopamine receptors, a change that takes weeks to occur. If so, then the direct moderation of dopamine in concert with serotonin and norepinephrine may be an efficient and faster way to alleviate depression.
Substance P Antagonists
Evidence from human and animal studies supports a role for substance P in mood regulation. First, recent studies indicate that substance P antagonists regulate monoamine activity in the brain stem, cause synaptic remodeling in the cortex, promote neurogenesis in the hippocampus, and regulate emotional pathways through the amygdala. Second, in animal studies, the number of substance P receptors declines following stress, presumably because stress provokes a release of substance P; the receptors adapt to the excess levels of the neuropeptide through a process called internalization (i.e., removal from the neuronal cell membrane).
In humans with depression, this adaptive process may be impaired, allowing the excess substance P to provoke the symptoms of depression. A few studies have shown that depressed patients have high levels of substance P in their cerebrospinal fluid, but other investigations have not confirmed this finding. Therefore, the level of substance P itself is not critical to the development of depression; most likely, a functional disturbance in systems that use substance P contributes to the disorder.
Substance P receptors are found in brain areas that are also rich in receptors for serotonin and norepinephrine; in animal studies, all three types of neurotransmitters have been implicated in the physiological response to stress. Research shows that substance P synthesis can be reduced by antidepressant drugs (e.g., selective serotonin reuptake inhibitors), but the mechanism by which these drugs affect substance P levels is unknown: antidepressant drugs show no significant affinity for the NK1 receptor, the receptor for which substance P shows affinity. Novel substance P antagonists have also shown antidepressant properties both in animal models of depression and in human trials.
Despite the disappointing cancellation of the development of Merck’s substance P antagonist MK-869 for depression, the development of substance P antagonists remains an active field, although publicly available information is limited. Merck has another substance P antagonist, L-759274, in Phase III development for major depression.
Esteve’s E-6006 remains in Phase Italy development in Spain for depression. GlaxoSmithKline is conducting a Phase II trial for anxiety and depression in the United Kingdom with its substance P antagonist vestipitant; the company expects to file in 2006. Roche’s R-673 is in Phase II development in Japan for depression and anxiety; the company also expects to file in 2006. Pfizer, however, has discontinued development of its NK1 antagonist CP-122721 because the observed benefit from the drug was not large enough to merit continuation of research. Furthermore, the company reports, it has ended development of the NK1 agonist CJ-17493.
Novel Hypotheses: The Hypothalamic-Pituitary-Adrenal Axis
Researchers are investigating whether the hypothalamic-pituitary-adrenal axis may be overactive in depressive disorders. More specifically, they suspect that in patients with depression, the adrenal cortex may release excess levels of cortisol, a glucocorticoid normally produced in response to stress. In support of this hypothesis, some studies have found that about 50% of patients with moderate or severe depression have elevated plasma concentrations of cortisol. Additionally, postmortem studies of the hypothalamic brain tissue of depressed patients have shown a fourfold increase in the number of neurons expressing corticotropin-releasing factor, a neuropeptide that stimulates the release of cortisol.
Researchers have not ascertained the causes of cortisol hypersecretion in depressed patients, but the abnormality appears to begin with an excess release of corticotropin-releasing factor. Researchers hypothesize that in people with depression, corticotropin-releasing factor stimulates the anterior pituitary to release an excess of adrenocorticotropic hormone (adrenocorticotropic hormone, also known as corticotropin), which in turn increases the responsiveness of the adrenal gland, resulting in excess secretion of cortisol.
In its indirect influence on cortisol hypersecretion, corticotropin-releasing factor acts as a neurohormone. It also acts as a neurotransmitter in limbic regions of the brain, structures that are involved in the regulation of mood and behavioral responses to stress. Of particular relevance to the study of depression are corticotropin-releasing factor neurons’ innervation of noradrenergic centers in the locus ceruleus and the amygdala because noradrenergic centers are implicated in the depressive cascade.
Two subtypes of corticotropin-releasing factor receptors have been identified: corticotropin-releasing factor 1, which is highly expressed in the pituitary and limbic structures and in other central nervous system regions; and corticotropin-releasing factor 2, which is located in the hypothalamus and limbic system but is more abundant in peripheral tissues. Researchers believe the corticotropin-releasing factor 1 receptor may have a larger role than the corticotropin-releasing factor 2 receptor in the pathophysiology of depression. They base this belief on preclinical studies showing that long-term administration of antidepressant drugs reduces the concentration of messenger RNA for corticotropin-releasing factor 1 receptors in the amygdala but does not have similar effects on the density of corticotropin-releasing factor 2 receptors.
Several studies have shown a reduction in corticotropin-releasing factor levels in the cerebrospinal fluid of depressed patients following treatment with antidepressant drugs or electroconvulsive therapy; these findings suggest that corticotropin-releasing factor reduction may be part of the drugs’ mechanism of action. Of particular interest are the findings of an investigation of corticotropin-releasing factor levels in 24 female inpatients with major depression.
An international group of researchers measured consistent corticotropin-releasing factor reductions only in patients who remained symptom-free for six months following antidepressant treatment. The researchers did not find consistent reductions in corticotropin-releasing factor in patients who suffered a relapse; indeed, corticotropin-releasing factor levels increased in some relapsed patients. These results suggest that when corticotropin-releasing factor levels return to baseline after antidepressant treatment, relapse may be imminent. Based on these and similar findings, some drug developers are pursuing therapies that inhibit the release of corticotropin-releasing factor.
Corticotropin-releasing factor Antagonists
Corticotropin-releasing factor antagonists are a radical departure from currently available monoamine-targeted antidepressants. corticotropin-releasing factor is a neurohormone that stimulates the release of adrenocorticotropic hormone, or corticotropin — in response to stress. adrenocorticotropic hormone increases the response of the adrenal gland, which results in the secretion of cortisol. Clinical research has shown increased levels of cortisol in some patients with depression. Furthermore, treatment with antidepressant drugs or ЕСТ reduces cortisol levels, suggesting that cortisol reduction may be a mechanism of the corticotropin-releasing factor antagonists’ antidepressant effects.
Corticotropin-releasing factor also acts as a neurotransmitter in limbic regions of the brain, where corticotropin-releasing factor neurons innervate noradrenergic centers in the locus coeruleus and amygdala. This role suggests a potential interaction between corticotropin and noradrenalin in the regulation of mood. In addition, data from animal models show that corticotropin-releasing factor-1-receptor antagonists block stress responses, an action that researchers interpret as evidence of their antidepressant and anxiolytic properties.
In August 2001, Neurocrine and GlaxoSmithKline signed a five-year, worldwide research, development, and commercialization agreement for corticotropin-releasing factor-receptor antagonists; this agreement included the codevelopment of NBI-34041, which is in Phase Italy trials for anxiety, depression, and irritable bowel syndrome. However, GlaxoSmithKline and Neurocrine are no longer collaborating on NBI-34041, although they are still collaborating on other compounds in the same class.
In early 2001, DuPont Pharmaceuticals was conducting a Phase Italy trial with its corticotropin-releasing factor 1 antagonist DPC-368; Bristol-Myers Squibb has since acquired the company, and the status of the program is unclear. A similar compound in development is Organon’s glucocorticoid antagonist ORG-34517. Designed to reduce cortisol levels, it is in Phase II trials in the United States and Europe for depression. Pfizer reports that it is midway through the development of a corticotropin-releasing factor antagonist called CP-316-311.
Current Therapies
No marketed antidepressants are approved to treat minor depression, but antidepressants such as citalopram (Lundbeck’s Cipramil, Forest Laboratories’ Celexa), fluoxetine (Eli Lilly’s Prozac), paroxetine (GlaxoSmithKline’s [GSK’s] Paxil, Seroxat), and sertraline (Pfizer’s Zoloft) have been in clinical trials for minor depression or dysthymia as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition proposed criteria or criteria that closely resemble these criteria. Of the antidepressants that have been investigated for minor depression, this section discusses in detail only the trials for fluoxetine and paroxetine because these drugs are the only two antidepressants that have been in randomized, placebo-controlled trials for minor depression in the adult population. Table 1 lists the drugs used to treat minor depression.
Although antidepressants — especially the selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors — have been under scrutiny by regulatory authorities because of the potential risk of suicide these agents pose, recent regulatory changes are not expected to significantly affect the treatment of minor depression in adults; the regulatory changes apply to minors only. After analyzing the results of a pooled analysis of short-term, placebo-controlled trials of 24 antidepressant trials in children and adolescents with major depression, the FDA was unable to conclude that any single antidepressant is free of suicidal risk.
Hence, in September 2004, the agency called for the labels of all antidepressants, including newer categories such as the selective serotonin reuptake inhibitors, the serotonin/norepinephrine reuptake inhibitors, and the older tricyclic antidepressants, to carry a black box warning about the risk of increased suicidal tendencies in young people. Of all the antidepressants on the market, only fluoxetine has been approved for use in depressed children and adolescents; several other antidepressants are prescribed to children off-label.
Selective Serotonin Reuptake Inhibitors
Serotonin-Norepinephrine Reuptake Inhibitors
Dopaminergic/Noradrenergic Agents
Tricyclic Antidepressants
Benzodiazepines
Overview
Benzodiazepines’ primary role in depression is adjunctive treatment to treat comorbid anxiety. Beginning with chlordiazepoxide in 1960, Benzodiazepines have been used effectively to treat anxiety for more than 40 years. These agents offer a rapid onset of action, providing nearly immediate relief from insomnia and other somatic symptoms associated with anxiety, such as muscle tension. All Benzodiazepines tend to induce habituation and dependence, making it difficult for patients to stop taking them. Because Benzodiazepines primarily affect somatic symptoms via their sedating properties, patients often report rapid relapse after discontinuation of therapy. Nevertheless, Benzodiazepines are associated with a relatively high response rate in treating comorbid anxiety: 70-80% of patients respond to Benzodiazepines.
Mechanism Of Action
Benzodiazepines bind to the gamma aminobutyric acid-A receptor; this binding leads to potentiation of the synaptic activity of gamma aminobutyric acid by prolonging the time during which the chloride channel is effectively open. gamma aminobutyric acid is the predominant inhibitory neurotransmitter in the brain; it suppresses neuronal activity and regulates the release of other neurotransmitters. In generalized anxiety disorder patients, a malfunction in the gamma aminobutyric acid system may contribute to reduction of gamma aminobutyric acid’s inhibitory activity, which researchers suspect plays a role in anxiety. In light of recent research that has identified specific subunits of the gamma aminobutyric acid-A complex as the mediators of the benzodiazepines’ anxiolytic action, drug developers are developing more specific benzodiazepine-like anxiolytics that have similar efficacy without the sedative-hypnotic effects.
Alprazolam
Alprazolam (Pfizer’s Xanax, Xanax XR, generics) has been used to treat symptoms of depression since the 1980s. However, few comprehensive studies have analyzed and quantified the efficacy of alprazolam in the treatment of minor depression, so this section does not discuss clinical trials evaluating the agent’s use in the treatment of depression. Instead, it focuses on studies covering alprazolam‘s use in the treatment of anxiety disorders.
Alprazolam is a rapid-acting Benzodiazepine with a short half-life. The original immediate-release (IR) formulation has proved effective in clinical trials in anxiety and has been effectively used to treat various types of anxiety for 20 years. Recently, an extended-release (XR) formulation of the drug has shown similar efficacy with an improved tolerability profile and simpler dosing. Patients taking the XR formulation of alprazolam require only once-daily dosing and achieve stable blood drug levels within the therapeutic range in three to six days; side effects are reduced as a result of lower peak drug levels.
Alprazolam may be as useful as the Benzodiazepine bromazepam (Roche’s Lexotan) in the treatment of patients suffering from minor depression and comorbid anxiety. In a four-week study (n = 121) that compared alprazolam XR (2mg once daily) with bromazepam (9 mg in three divided doses), the two drugs elicited similar response rates: more than 70% of patients responded by week 3 of treatment. During the fourth week, when patients were tapered off their medication, discontinuation-related effects were mostly mild and did not differ in the two groups.
Adverse events most commonly associated with alprazolam include central nervous system-related events such as drowsiness, sedation, and dizziness, but these side effects rarely lead to discontinuation of therapy. Much more difficult for patients to tolerate are the withdrawal effects — e.g., rebound anxiety, insomnia, memory lapse — that occur with all Benzodiazepines.
Psychostimulants
Overview
Psychostimulants, such as methylphenidate (Novartis’s Ritalin/ Ritaline/Ritalin-SR/Ritalin-LA, Celltech’s (now part of UCB) Metadate ER/ Metadate CD, Alza/McNeil Consumer Healthcare/Janssen-Cilag’s Concerta/ Concerta XL, generics), are sometimes used as adjunctive therapy for the treatment of depressive disorders.
Mechanism Of Action
Although psychostimulants exert a calming effect on patients with attention-deficit/hyperactivity disorder, they can increase activity in patients without attention-deficit/hyperactivity disorder — hence their increasing popularity in treating depressed patients with symptoms of fatigue, sedation, and weight gain. Methylphenidate is the most popular psychostimulant used to treat depression. The main concerns about psychostimulants are their potential for sensitization and abuse and diversion to nonpatients for recreational use. Side effects of stimulants include nervousness, insomnia, and weight loss.
Methylphenidate
Methylphenidate’s mechanism of action is not fully understood, but the main theory holds that the drug acts on the dopamine transporter protein, which usually serves to transport dopamine into presynaptic nerve cells. When dopamine reuptake is slowed by the administration of low doses of the drug, it accumulates in the extracellular space between nerve cells. At first, the increased dopamine stimulates receptors and boosts locomotor activity, but these actions are quickly regulated by a negative feedback loop that slows the pulsatile release of dopamine from presynaptic nerve cells. This reduction causes a corresponding decline in locomotor activity. Methylphenidate also binds to the norepinephrine transporter to inhibit norepinephrine uptake in the intracellular space.
To date, no large placebo-controlled trials have evaluated methylphenidate’s use in the treatment of depressive disorders. However, one small trial does indicate that methylphenidate may be useful as an adjunctive therapy with the selective serotonin reuptake inhibitors. In a small (n = 11) open-label trial examining the potential of methylphenidate to accelerate the response of citalopram in an elderly population, six of the nine patients who completed the trial met the criteria for accelerated response.
Emerging Therapies
More than 80 compounds are in clinical development for the treatment of depressive disorders (i.e., major depression, bipolar depression, psychotic depression), but none of these agents is in clinical trials for minor depression.
Only a handful of well-controlled drug trials have been conducted in patients with minor depression, and studies that have targeted patients whose symptoms closely resemble the proposed criteria for this indication of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition have been designed primarily with a view toward validating this proposed diagnostic category rather than identifying the most efficacious treatment. Since 1990, only paroxetine and fluoxetine have been tested in well-controlled, randomized trials of depressive disorders similar to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition proposed criteria. (A 1988 study of amitriptyline in minor depression showed no difference compared with placebo following a six-week course of treatment.)
The lack of drug development is only partly due to the lack of formal diagnostic criteria for minor depression. Developers likely shy away from testing a drug for minor depression because antidepressants approved for other, more discrete and well-defined forms of depression can garner considerable off-label earnings in the market for minor depression; the investment (and risk) of pursuing a label for minor depression is therefore not necessarily worthwhile. Also, showing a treatment effect in minor depression is presumably even more difficult than showing a treatment effect in major depression.
Few minor depression trials have shown that treatment with antidepressants is superior to treatment with placebo or other interventions (e.g., cognitive-behavioral therapy) in all but the most severely affected patients. To reduce the probability of attaining statistically insignificant results, investigators designing trials of minor depression often use inclusion criteria that are more stringent than the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition proposed criteria.
Despite these risks, it is reasonable to assume that companies will pursue formal labeling for minor depression, probably as an add-on indication following approval for major depression. The strategy of adding indications to current drug labels is a standard means of extending antidepressant products’ life cycles and competing in this crowded and mature market.
This section discusses in detail agents in clinical development that have potential to garner significant sales in the minor depression market within the next ten years.
TABLE. Nonpharmacological Techniques Under Study for Treatment of Drug-Refractory Depression
Techniques | Description | Application to Depression |
Deep brain stimulation (DBS) | A surgical procedure requiring the implantation of an electrode deep in the brain; this electrode is connected to a pacemaker-like device in the patient chest. The pacemaker-like device generates a steady current in the brain region where the tip of the electrode is located. | Approved in the United States in 2002 and in Europe in 1998 for the treatment of Parkinson’s disease. DBS of the ventral caudate nucleus could be a promising strategy in the treatment of refractory cases of both obsessive-compulsive disorder (obsessive-compulsive disorder) and major depression. |
Repetitive transcranial magnetic stimulation (rTMS) | A noninvasive, experimental technique used to stimulate the brain using strong pulsed magnetic fields; these magnetic fields create a current flow in the brain and can temporarily excite or inhibit specific areas of the brain and alter the functioning of the brain beyond the time of stimulation, offering potential for therapy. | May be useful in the treatment of depression, but results from trials have been inconclusive to date. Moreover, research appears to be focused on treatment-resistant depression. |
Vagus nerve stimulation (VNS) | A small device controlled externally by a magnetic wand and connected with a wire to the vagus nerve. At regular intervals the VNS device sends tiny electrical pulses to the vagus nerve, which is thought to stimulate the deep areas of the brain where seizures and other maladies begin. | Approved by the FDA in 1997 for the treatment of treatment-resistant epilepsy. Approved in Europe and Canada for treatment-resistant depression. |
Excluded from the discussion here are nonpharmaceutical technologies that have shown promise in depression; these strategies have the most promise in patients who fail to respond to all lines of drug therapy and, as such, are unlikely to affect sales of drug therapy. Table 4 lists the most promising emerging therapies in development.
The FDA will likely require all antidepressants entering this market to carry the black box warning cautioning against the use of antidepressants in children and adolescents at risk for committing suicide. An exception to this rule may be a drug with a faster onset of action because it is the delay to onset that increases the risk of suicide, especially in pediatric patients.
Although the triple-reuptake inhibitors and 5-HT antagonists (especially when used together with a selective serotonin reuptake inhibitor ) are hypothesized to have a faster onset of action, the fact that their mechanisms of action are similar to those of other monoamine antidepressants and antidepressant combinations (e.g., bupropion and an selective serotonin reuptake inhibitor, pindolol and a serotonin-norepinephrine reuptake inhibitor) that carry the FDA-mandated black box warning reduces the chance they will launch without the warning on their labeling.
TABLE . Emerging Therapies in Development for Minor Depression
Compound | Development Phasef) | Marketing Company | |
Serotonin-norepinephrine reuptake inhibitors | |||
Duloxetine (Cymbalta ) | |||
United States | R | Eli Lilly | |
Europe | R | Eli Lilly/Boehringer Ingelheim | |
Japan | PR | Eli Lilly/Shionogi | |
Desvenlafaxine | |||
United States | III | Wyeth | |
Europe | – | – | |
Japan | — | — | |
LIF-247 | |||
United States | Ill | Enhance Biotech | |
Europe | – | – | |
Japan | — | — | |
Triple reuptake inhibitors | |||
DOV-216303 | |||
United States | Italy | Merck | |
Europe | II | Merck | |
Japan | – | – | |
NS-2359 | |||
United States | — | — | |
Europe | II | Neurosearch/GlaxoSmithKline | |
Japan | – | – | |
Dopaminergic/noradrenergic agents | |||
Radafaxine | |||
United States | — | — | |
Europe | II | GlaxoSmith Kline | |
Japan | – | – | |
SLV-308 | |||
United States | — | — | |
Europe | II | Solvay | |
Japan | — | — | |
5-HT agonists/antagonists | |||
Agomelatine | |||
United States | — | — | |
Europe | Ill | Servier | |
Japan | — | — | |
AZD-8129 | |||
United States | — | — | |
Europe | II | AstraZeneca | |
Japan | – | – | |
Elzasonan | |||
United States | II | Pfizer | |
Europe | – | – | |
Japan | — | — | |
Adrenergic agonists | |||
SR-58611 | |||
United States | — | — | |
Europe | Ill | Sanofi-Aventis | |
Japan | – | – | |
NK antagonists | |||
L-759274 | |||
United States | III | Merck | |
Europe | – | – | |
Japan | — | — | |
Vestipitant/paroxetine соmbination | |||
United States | — | — | |
Europe | II | GlaxoSmith Kline | |
Japan | – | – | |
Monoamine oxidase inhibliters | |||
Transdermal selegiline | |||
United States | PR | Somerset/Bristol-MyersSquibb/Watson Pharmaceutical | |
Europe | – | – | |
Japan | – | – |
Serotonin-Norepinephrine Reuptake Inhibitors
Triple Reuptake Inhibitors
Dopaminergic/Noradrenergic Agents
5-HT Agonists/Antagonists
Adrenergic Agonists
Overview
The adrenergic receptors mediate excitatory and inhibitory responses. Divided into the alpha and beta subtypes, these receptors are further classified by their affinity for different agonists and antagonists; some agonists are in development for the treatment of depression. Sanofi-Aventis’s SR-58611, which entered Phase III trials in September 2003, is an example of a highly selective agonist for beta-3-adrenoreceptors under investigation for the treatment of major depression.
The agent acts indirectly as a noradrenergic agent, preventing the reuptake of nore-pinephrine. (Similar agents are also under investigation for the treatment of obesity and type 2 diabetes; the majority of these agents are in preclinical development.) Modafinil (Cephalon’s Pro vigil) is an alpha-1-adrenoreceptor agonist marketed for the treatment of narcolepsy and idiopathic hypersomnia and in development for sleep apnea, fatigue associated with various neurological disorders, and attention-deficit/hyperactivity disorder and as monotherapy or adjunctive therapy for the treatment of depression.
Mechanism Of Action
Beta-3-adrenoreceptors are located primarily in adipose tissue and are involved in lipolysis, thermogenesis, and gastrointestinal motility functions. In rodent models, in response to norepinephrine, they stimulate metabolism and peripheral burning of fat. Because these agents indirectly inhibit norepinephrine reuptake, they are expected to have an antidepressant effect.
SR-58611
SR-58611 is a beta-3-adrenergic-receptor agonist in Phase III development by Sanofi-Aventis for the treatment of major depression. The compound was also in development for type 2 diabetes, obesity, and irritable bowel syndrome, but development is now focused strictly on the treatment of major depression.
SR-58611 is an indirect noradrenergic agent that inhibits norepinephrine reuptake via agonism of the beta-3-adrenoreceptor. Researchers theorize that symptoms of depression result from poor uptake of monoamines (norepinephrine as well as serotonin and dopamine) by postsynaptic transporters. Leftover monoamines are reabsorbed by the presynaptic cell; consequently, the presy-naptic cell releases fewer monoamines into the synaptic cleft. The net result is a monoamine deficit in the synaptic cleft. SR-58611 corrects the deficit of norepinephrine by blocking the reuptake of the monoamine by presynaptic cells.
The release of clinical data from trials of SR-58611 for the treatment of major depression has been limited; the most advanced clinical trial data were released at a 2003 Sanofi-Synthelabo informational meeting. In a comparator trial, 300 mg and 600 mg of SR-58611 were compared with 20 mg of paroxetine in patients (n = unknown) with recurrent major depression and melancholia. Response to treatment was measured using the HAM-D scale. At the trial end point, the response rates in patients who received 300 mg or 600 mg of SR-58611 or 20 mg of paroxetine were 60%, 75%, and 57%, respectively. At week 6, 40% of the patients receiving 600 mg of SR-58611 had a total score of less than 8, compared with 24% and 23% of patients who were given 20 mg of paroxetine or 300 mg of SR-58611. Of the patients treated with 600 mg of SR-58611, 21% experienced mild treatment-associated adverse events, compared with 25% of the paroxetine -treated patients.
Neurokinin Antagonists
Monoamine Oxidase Inhibitors
Overview
Monoamine oxidase inhibitors are available in the U.Spain. and European markets. Somerset Pharmaceuticals, Watson Pharmaceutical, and Bristol-Myers Squibb’ s Monoamine Oxidase Inhibitor transdermal selegiline is preregistered for approval for major depression in the U.Spain. market and is therefore discussed among the emerging therapies.
Although Monoamine Oxidase Inhibitors are highly effective in the treatment of depression (particularly atypical and treatment-resistant depression), the original Monoamine Oxidase Inhibitors such as phenelzine (Warner-Lambert’s Nardil, generics) and tranylcypromine (GSK’s Parnate, generics) are associated with potentially serious side effects, including cardiotoxicity, dangerous interactions with tyramine-containing foods, and interactions with numerous other drugs. In the 1960s, following several deaths from brain hemorrhage that resulted from hypertensive episodes caused by tyramine-Monoamine Oxidase Inhibitor interactions, these agents were temporarily taken off the U.Spain. market. Less serious side effects include weight gain, edema, insomnia, muscle cramps, sexual dysfunction, dizziness, and orthostatic hypotension.
Companies have expended much effort to improve the Monoamine Oxidase Inhibitors since their introduction. Monoamine oxidase exists in two major forms — Monoamine oxidase-A and Monoamine oxidase-B — which are distinguished by their substrate affinities for norepinephrine and serotonin (A form) or dopamine (B form). The original Monoamine Oxidase Inhibitors were nonse-lective, irreversible inhibitors of both Monoamine oxidase-A and Monoamine oxidase-B.
Extensive research has since revealed that inhibition of Monoamine oxidase-A is primarily responsible for the antidepressant effects of the Monoamine Oxidase Inhibitors and that the dangerous tyramine-Monoamine Oxidase Inhibitor interactions that accompany Monoamine oxidase-A inhibition can be significantly attenuated by using reversible inhibitors of Monoamine oxidase-A. A popular agent in this class is moclobemide (Roche’s Aurorix), a short-acting, reversible inhibitor of Monoamine oxidase.
Mechanism Of Action
Monoamine Oxidase Inhibitors restore serotonin and norepinephrine function by blocking Monoamine oxidase, a naturally occurring enzyme that metabolizes monoamines such as serotonin and norepinephrine. Clinical trials show these agents are equal in efficacy to selective serotonin reuptake inhibitors and tricyclic antidepressants.
Transdermal Selegiline
Somerset Pharmaceuticals, Watson Pharmaceutical, and Bristol-Myers Squibb’s transdermal selegiline (Emsam) is preregistered in the United States for the treatment of major depression and is in Phase III trials for Alzheimer’s and Parkinson’s diseases; it is also in Phase Italy for attention-deficit/hyperactivity disorder. (Oral selegiline [Somerset’s Eldepryl, Orion’s Deprenyl/Movergan, Chiesi’s Egibren, Viatris’s Plurimen, Amarin’s Zelapar, generics] is already approved in the United States for adjunctive use with levodopa/carbidopa in the treatment of Parkinson’s disease.)
The FDA deemed Somerset’s 2002 new drug application for transdermal selegiline in major depression not approvable, but in August 2003, the agency accepted the filing after the company submitted additional clinical data. The reasons for the initial nonapprovable designation are unclear. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement to distribute and commercialize transdermal selegiline for major depressive disorder. Under the terms of the agreement, Bristol-Myers Squibb receives exclusive distribution rights to commercialize transdermal selegiline, if approved, in the United States and Canada, with an opportunity to negotiate, within a specified time frame, rights in any or all of the rest of the world.
Transdermal selegiline is an Monoamine oxidase-B inhibitor. Inhibition of Monoamine oxidase-B interferes with the breakdown of dopamine in the brain and thus maintains circulating levels of dopamine, thus easing depression in some patients. Because transdermal selegiline lacks serotonergic effects, the agent is potentially free from side effects such as sexual dysfunction, weight gain, and sedation.
Transdermal selegiline has been proved effective for the treatment of major depression. In a six-week study, outpatients (n = 177) with major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) who were on a tyramine-restricted diet were given either 20 mg of selegiline, applied once daily by means of a 20 cm2 patch, or a placebo patch. In this study, the primary measure of efficacy was a reduction in the 17-item and 21-item HAM-D for depression, the MADRS, and the Clinical Global Impressions scale. The Medex Depression Evaluation Scale, a self-report instrument devised for this study, was used to assess change in sexual function during treatment. At end point, transdermal selegiline was significantly better than placebo in the treatment of major depression symptoms according to all measures.
Moreover, patients taking transdermal selegiline exhibited significantly improved sexual function compared with patients taking placebo. No significant adverse events were observed in the two groups except for application site reaction (e.g., rash, itching, redness), which was most common in patients treated with the active drug. Side effects often associated with oral selegiline treatment (e.g., blood pressure elevation, flushing, headache, lightheadedness, orthostatic hypotension, tachycardia) were not observed. Researchers also noted the drug’s early onset of action: at week 1, patients taking transdermal selegiline experienced greater reductions in the 17-item and 28-item HAM-D and the MADRS than did patients receiving placebo.
Because patients were on a tyramine-restricted diet, the risk of a “cheese reaction” was minimized. Oral Monoamine Oxidase Inhibitors inhibit the Monoamine oxidase-A enzymes in the gut that detoxify dietary tyramine in fermented products such as cheese, red wine, and soy sauce; ingesting these fermented products while taking Monoamine Oxidase Inhibitors can cause acute hypertension, an event that can be fatal. However, the study researchers hypothesize that because its transdermal delivery limits the drug’s exposure to the gastrointestinal tract, selegiline does not interfere with Monoamine oxidase in the digestive system and therefore does not interfere with tyramine detoxification.
However, transdermal selegiline may carry dietary restrictions on its label that will limit its use to last-resort therapy by psychiatrists, who are familiar with Monoamine oxidase inhibitors and their safety risks. Furthermore, although Somerset received an approvable letter from the FDA for its transdermal selegiline, the agency suggested that Somerset conduct Phase IV pharmacokinetic and safety studies as well as additional pharmacology/toxicology studies to monitor the drug’s safety.
Although selegiline transdermal treatment offers the advantages of early onset of action and apparent freedom from sexual side effects, the drug’s antidepressant efficacy likely depends on an Monoamine oxidase-A inhibition that is achieved only when the drug is administered in doses higher than the oral doses used for Parkinson’s disease (5mg), a situation that will make the drug unsafe when combined with tyramine-rich foods. Dietary restrictions on the drug’s label will severely limit its use.
He knows everything about medications – to which pharmacological group the drug belongs, what components are included in its composition, how it differs from its analogs, what indications, contraindications, and side effects remedy has. John is a real pro in his field, so he knows all these subtleties and wants to tell you about them.