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FOCUS, VOL. 3, No. 1

REVIEW | January 01, 2005

Recent Studies of the Biology and Treatment of Depression

Alan F. Schatzberg, M.D.

From the Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Stanford, California.

FOCUS 2005;3:14-24.

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AcknowledgmentThis paper was supported by grant MH 50604 from the National Institute of Mental Health.

CME Disclosure StatementAlan F., Schatzberg, Chairman, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.

Consultant/Speaker: Abbott, Aventis, Bristol-Myers Squibb, Corcept, Lilly, Forest, GlaxoSmithKline, Innapharma, Janssen, Merck, Novartis, Organon, Pharmacia, Solvay, Somerset, Wyeth. Grants: Bristol-Myers Squibb, Lilly, Wyeth. Equity: Corcept, Cypress Biosciences, Elan, Merck, Pfizer. Co-founder: Corcept Therapeutics. Co-inventor: intellectual property owned by Stanford University.

Disclosure of Unapproved, Off-Label, or Investigational Use of a ProductAPA policy requires disclosure by CME authors of unapproved or investigational use of products discusssed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by the scientific literature and clinical experience. This article contains discussion of mifepristone for psychotic depression; MK-869 for major depression; selegiline patch for depression; and R121919 for depression.

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Abstract

Major depression is one of the most common psychiatric disorders, with lifetime prevalence rates of over 15%. Recent research provides new insights on which brain regions are affected in the disorder, underlying biological mechanisms, and possible novel treatments. This review discusses a number of recent research advances in epidemiology, genetics, imaging, treatment, and pharmacogenetics. It also outlines issues or questions that still need to be addressed, and it begins to outline a framework for understanding why and how depression may occur.

Figures in this Article

Epidemiology and Course

Depression is a common disorder. The National Comorbidity Survey reported a prevalence rate of 5% for current depression and a lifetime rate of 17% (1). Some investigators have noted that these rates are higher than those seen in the Epidemiologic Catchment Area (ECA) survey (2), suggesting an overinclusion of milder forms of depression. Indeed, a reassessment and follow-up study using more clinically relevant definitions of severity of illness yielded rates of depression subgroups that are more consonant with other reports as well as clinical impressions (2, 3). Still, major depression is a common disorder not only in the United States but in all societies, and even milder forms carry considerable morbidity (3). Indeed, the World Health Organization/World Bank Study ranked unipolar depression the fourth highest cause of morbidity in 1990, with the expectation that by 2020 it would become the second leading cause of disability (4, 5).

Several recent studies have explored specific subtypes of depression. For example, atypical features as defined in DSM-IV-TR have been a focus of a number of epidemiological and clinical studies (6, 7). Parker and colleagues (6), in Australia, reported that the absence of mood reactivity appeared to be associated with severity of depression and that other atypical symptoms (e.g., hyperphagia) did not appear to be related to each other, raising questions about the validity of the subtype. Others, however, have observed that atypical features do coalesce (7, 8), so this issue remains subject to debate.

Psychotic major depression was the focus of one analysis of a large European survey involving some 19,000 subjects in five countries (9). Psychotic features were found in nearly 19% of subjects who met criteria for a major depressive episode (MDE), a rate slightly higher than the 15% reported in the ECA study. Psychotic features were most commonly seen in individuals who endorsed eight or nine items of the criteria for major depression (33%), but they were also seen in individuals with milder forms of MDE.

Alternative presentations of MDE have increasingly become a research focus, for several reasons, including the common presentation of MDE as physical complaints in primary care and the efficacy of several psychotropic agents in both mood and anxiety disorders as well as chronic pain. Many patients with MDE in primary care settings present with complaints of physical symptoms, including pain (10). Although pain is commonly observed in MDE in primary care settings, there has been considerable skepticism about the generalizability to epidemiological community samples or to psychiatric practices.

In the large European sample mentioned above, chronic painful physical symptoms were observed in 16% of the general population but in 43% of subjects who met criteria for MDE (11). Less than half of the respondents who reported MDE and chronic pain symptoms had an identifiable organic cause of their pain. Headache (including neck pain), shoulder pain, and backache were the most common types of pain. Compared with DSM-IV-TR criteria for MDE, chronic painful symptoms were more commonly seen in subjects with MDE than was guilt, and nearly as commonly as loss of energy. These data have been recently replicated in a study in California (unpublished 2004 study of M. M. Ohayon). Consideration should be given to including chronic pain symptoms in the criteria for major depression in future classification schemes.

As more effective medication and psychotherapy strategies have been developed, greater attention has been given to the significance of residual symptoms that do not meet full criteria for MDE; patients with such residual symptoms have been termed partial responders and their illnesses subsyndromal disorders. Analyzing outcome data from the National Institute of Mental Health (NIMH) Collaborative Program on the Psychobiology of Depression (Collaborative Depression Study), Judd and colleagues (12, 13) reported that residual depressive symptoms are associated with a higher risk of relapse or recurrence, greater utilization of medical services, and greater risk of substance abuse. Thus, increasing attention has been given to maximizing response to both somatic and psychosocial interventions (discussed further below).

A number of explanations have been proposed for the continuation of depressive symptoms despite treatment. Paykel’s group (14) reported a decade ago that residual physical symptoms of depression were associated with a greater likelihood of relapse or recurrence. More recently, Fava and associates (15), in a pooled analysis of studies of duloxetine (a dual norepinephrine/serotonin reuptake inhibitor), reported that remission of depressive symptoms was highly associated with improvement in pain symptoms. Thus, focusing on both physical and emotional symptoms in depression could provide added benefit. Prospective large-scale studies comparing dual uptake agents and selective serotonin reuptake inhibitors (SSRIs) in depressed patients with comorbid pain could help illuminate this area.

Another area that has attracted attention is the role childhood abuse may have in adult major depression and response to treatment. Our group has reported that in chronically depressed patients with early abuse, a specialized form of psychotherapy (cognitive behavioral analysis system of psychotherapy—CBASP) was more effective than nefazodone (16), whereas the opposite was seen in nonabused patients. Early abuse has also been reported to be associated with an increased risk of depression, comorbid pain, and utilization of medical services in health maintenance organization (HMO) settings (17). Thus, research data appear to be converging on an important adult medical phenomenon with roots in childhood.

Genetics

The genetics of major depression has been a focus of a great deal of research over the past several decades. For much of that time, linkage studies failed to establish clearly any single candidate gene, which led investigators to argue that depression represented a complex genetic disorder, to which many different genes could potentially contribute, either alone or in combination with other genes or with environmental factors such as stress. Recently a number of interesting candidate genes have been identified, primarily from population-based or case-control studies. Several of these genes point to potential interactions with stress.

The short form of the promoter for the serotonin (5-HT) transporter was reported a number of years ago to be associated with neurotic traits. Although subsequent studies did not find a genetic risk of depression in subjects with a short promoter (18), the short form has been associated with increased amygdala activation with stress (19). In the past few years, the short form has also been reported to predict poor response or intolerance to SSRIs in Caucasians in Europe and in the United States (see Pharmacogenetics below). In a major longitudinal study in New Zealand that followed subjects from childhood (18), the short form of the promoter by itself was again not found to be associated with increased risk of depression in the absence of stressors; similarly, stressors by themselves did not predict major depression. However, a significant gene-by-stress interaction was noted, with s/s homozygotes for the transporter promoter at greater risk of developing depression if three or more stressful life events were encountered. This could be a major lead in our understanding of the interaction between biological risk and psychosocial precipitants.

Stress activates both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The ability to turn off the HPA axis via feedback mechanisms is widely believed to be a key feature of healthy adaptation, and individuals who are less able to moderate their stress response may be more prone to depression. Feedback inhibition is mediated in part via the glucocorticoid receptor in the hypothalamus, hippocampus, and pituitary. This receptor is surrounded by chaperone heat shock proteins (HSPs), one of which (HSP90) has been implicated in increasing the risk of depressive episode as well as predicting more rapid response to antidepressant treatment. Multiple single-nucleotide-polymorphism genotypes of the FKBP5 gene were explored in two German cohorts. Patients with the T/T genotype at rs1360780 demonstrated more than twice as many depressive episodes as did the C/T or C/C subtypes (20). This T/T genotype is associated with increased expression of the FKBP5 protein, which may result in glucocorticoid receptor insensitivity. However, direct study of patients with the T/T genotype did not point to their having more elevated cortisol levels, and they demonstrated more rapid responses to antidepressant treatment. Thus, although the exact role of this gene or protein in depression remains to be elucidated, the gene is clearly worthy of further study.

Decreased serotonin activity has long been thought to play a key role in the pathophysiology of depression and response to treatment. Serotonin is synthesized from tryptophan via a tryptophan hydroxylase. Recently Zhang et al. (21) and Patel et al. (22) elegantly demonstrated that neuronal synthesis of serotonin is controlled largely via tryptophan hydroxylase 2 (TPH-2) and not the 1 form, which was formerly thought to regulate synthesis in the brain but is now seen to be involved mostly in the periphery. This observation was recently supported by a report that a mutation in TPH-2 was found in some 10% of subjects with unipolar major depression, compared with 1.5% of control subjects (23). This mutation was associated with an 80% decrease in serotonin levels when expressed in a cell line. The variant was not observed in a cohort with bipolar illness. Thus, at least some depressions may be due to a gene variant associated with low serotonin activity. Whether this TPH-2 gene can be used to predict response to SSRI treatment has not yet been studied.

In two of the three genes discussed above, stress could play an important role in interacting with a genetic risk to lead to a depression. In the third gene, decreased synthesis of an important brain neurotransmitter could reflect a specific genetic variant.

Brain imaging

Structural imaging

In the past decade, hippocampal volume has become a focus of much research in MDE. The impetus has been the work of Sapolsky and of McEwen (24, 25) showing that stress and glucocorticoids could be neurotoxic and lead to hippocampal neuron loss in lower animals. A related finding is that antidepressants appear to increase neurogenesis in the hippocampus, which some have argued may be a key mechanism of action for these medications (26, 27).

Smaller hippocampal volume has been reported in depressed patients in several studies (28—33) but not others (34—37). A recent meta-analysis suggested that hippocampal volume is lower in depressives if one does not include the amygdala in the volume analysis (38). The findings of these various studies are summarized in Table 1.

A number of other factors could also affect volumetric differences. Sheline and colleagues reported a significant negative correlation between hippocampal volume and total duration of depression, but not age (39). They argued that this finding may reflect chronic exposure to stress, which is consistent with basic research suggesting that glucocorticoids could be neurotoxic. In addition, Vythilingam and colleagues reported that depressed patients with a history of early child abuse had smaller hippocampi than did healthy controls (32), which is consistent with an effect of cortisol on hippocampal volume.

This hypothesis has been appealing to many investigators, but earlier data from Axelson and colleagues showed no relationship between cortisol activity and hippocampal volume (40). A number of other perspectives suggest that lower hippocampal volume could be a risk factor for depression rather than a result of it (41). For one thing, hippocampal volume is largely genetically determined (42—44). Our group reported that genetics exerted a greater effect on hippocampal volume than did early stress in squirrel monkeys (42). Sullivan and colleagues (43) and Pitman’s group (44) reported a significant effect of genetics on hippocampal volume in twin studies. These three studies all point to strong genetic influences on hippocampal volume.

Other data point to smaller hippocampal volume presaging untoward outcomes. First-episode, younger depressives already had smaller hippocampi than control subjects in a German study (31). In a Veterans Administration study of posttraumatic stress disorder (PTSD) in twins (44), identical twins who were discordant for trauma exposure had similar hippocampal volumes; subjects with smaller hippocampi were more likely to develop PTSD if exposed to combat. These data all suggest hippocampal volume is related to risk of depression. Indeed, another recent study reported smaller hippocampi in depressives with l/l genotype for the 5-HT transporter (45). This finding does not entirely fit with the Caspi et al. (18) finding that the s/s form of the gene was associated with risk of depression in the face of stress. In spite of these findings suggesting that small hippocampal volume is a risk factor for MDE, depression and stress could still result in a further diminution of hippocampal size. For example, Brown and colleagues reported that medical patients taking steroids had smaller hippocampi than did medical control subjects (46). Debate in this area is likely to continue until longitudinal studies with magnetic resonance imaging and cortisol status are undertaken with depressed subjects or their at-risk offspring.

Functional imaging

Functional imaging studies suggest that hippocampal activity may be disordered in depression. A number of groups early on reported verbal memory impairment in the disorder (47, 48); however, my colleagues and I reported that generally nonelderly psychotic depressives—but not nonpsychotic depressives—demonstrated impairment in verbal memory compared with healthy controls (49). In the same study, we reported a marked impairment in an attention/response inhibition task in psychotic depressives—indicative of prefrontal/anterior cingulate involvement—and suggested a connection between these deficits. Bremner and colleagues (50) recently reported that verbal memory impairment in depression is associated with difficulty in activating both the hippocampus and the anterior cingulate using position emission tomography (PET). They suggested a possible circuit involving the prefrontal cortex, anterior cingulate, and hippocampus in depression (50).

Decreased prefrontal activity in depression using PET is a well-established finding (51—53). Of particular interest is the work of Drevets and Mayberg showing that the subgenual cortex (inferior/posterior aspect of the frontal lobe) is activated during sadness induction in depression, that it may be significantly reduced in volume, and that its activity may change in response to antidepressants (54—56). This area is a focus of possible therapeutic intervention using direct activation approaches such as deep brain stimulation.

Psychopharmacology

Just a few years ago my colleagues and I commented in the fourth edition of the Manual of Clinical Psychopharmacology that the horizon seemed bright for antidepressant agents with new mechanisms of action (57). However, a number of then-promising agents have not received approval from the Food and Drug Administration (FDA), and the near-term horizon seems quite a bit dimmer. Promising approaches are summarized in Table 2.

Duloxetine

The most recently approved antidepressant is duloxetine, a serotonin/norepinephrine reuptake blocker with dopamine reuptake effects as well. Duloxetine has been shown to be significantly more effective than placebo in major depression in several studies (58—60). Dosages studied have ranged from 40 mg/day to 120 mg/day, and the recommended daily dose is now 60 mg/day. Duloxetine’s half-life is approximately 14 hours. There are no data to indicate that doses above 60 mg/day are more effective than the recommended dose. Although the package insert indicates that the dosage can be started at 60 mg/day, many clinicians have their patients start with 30 mg/day and increase the dose to 60 mg/day after approximately 1 week. This approach can help reduce the likelihood that patients will experience duloxetine’s most common side effect, nausea, which is seen in as many as 40% of patients begun on 60 mg/day. Accommodation to nausea often occurs by the end of the first week. Other common side effects include dry mouth, constipation, and sedation. Hypertension is seen relatively infrequently (61).

As noted earlier, major depression is frequently comorbid with chronic pain, often without organic cause. Duloxetine appears to improve both depression and painful physical symptoms, particularly backache and shoulder pain. It is thought that descending norepinephrine and serotonin fibers from the brain via the spinal cord serve to dampen peripheral pain signals. Increased norepinephrine and 5-HT "tone" may thus simultaneously improve mood and comorbid pain. As mentioned above, Fava and associates (15) reported that remission of depression is more likely if pain symptoms are also markedly improved. My colleagues and I recently reported that in one study duloxetine was significantly more effective than placebo in reducing pain in depressed patients with comorbid pain but that the drug did not separate from placebo on reduction of depression (62). These data suggest that the drug can reduce chronic pain (independent of effects on depression) and are consistent with preclinical data (63).

Indeed, duloxetine was the first drug approved for treatment of diabetic neuropathic pain, although it does not provide acute analgesic effects. At doses of 60—120 mg/day it is significantly more effective than placebo in reducing pain in nondepressed patients. Recently the drug has also been reported to improve pain symptoms in patients with fibromyalgia, particularly women (64).

Enhanced norepinephrine/serotonin activity may improve bladder control in women with stress urinary incontinence disorder (65). Duloxetine has been approved for this use in Europe, and it is expected to receive similar approval soon in the United States.

Abrupt discontinuation of antidepressants is frequently associated with rebound symptoms. This was originally reported with tricyclics, cessation of which can cause rebound peripheral cholinergic symptoms (abdominal cramping, headaches, and the like); in addition, psychiatric symptoms (hypomania and mania) were reported by our group and others in the 1980s (57, 66, 67). With the advent of the SSRIs, discontinuation symptoms were observed anew, particularly with the short-acting, more potent 5-HT reuptake blockers (68, 69). Symptoms include a flulike syndrome with vertigo, nausea, paresthesias, and mood changes. These symptoms have also been observed with the mixed reuptake blockers and have been reported in about 15% of patients treated with duloxetine in clinical trials. When discontinuing the agent, a gradual reduction from 60 mg/day to 30 mg/day for at least 1 week is recommended.

Transdermal selegiline patch

Selegiline is an irreversible monoamine oxidase (MAO)-B inhibitor that has long been approved at low doses (5—10 mg/day orally) for the treatment of Parkinson’s disease. At oral doses of 20 mg/day or higher, the drug is an effective antidepressant agent; however, at these doses it is an inhibitor of both MAO A and B and hence is prone to interactions with dietary foodstuffs (70). Delivery of selegiline via a transdermal patch avoids major inhibitory effects on intestinal MAO-A and thus obviates the need for dietary restrictions. This is particularly the case at the lower doses, such as via a 20 mg or 30 mg patch daily. At 40 mg/day an interaction is theoretically possible but highly unlikely. When delivered transdermally the drug appears to produce both MAO A and B inhibition in the brain (71), which is somewhat similar to the action of tranylcypromine. Because of its MAO A and B effects in the brain, patients need to be warned about avoiding concomitant use of other agents, such as meperidine, SSRIs, and so on, even though diet may not pose a problem.

Selegiline transdermal patch has been shown to be more effective than placebo in improving depressive symptoms in patients with either typical or atypical subtypes of depression. The starting dose is 20 mg applied daily, with increases to a recommended maximum of 40 mg/day. At 20 mg/day the drug is more effective than placebo but not dramatically so (72). In a pivotal trial using flexible dosing of 20—40 mg/day, more dramatic separation from placebo was seen, suggesting that higher doses may have greater efficacy.

A principal side effect of selegiline is irritation at the site of application. In addition, because the drug is metabolized to amphetamine or d-amphetamine, it may be quite stimulating, and some patients have difficulty sleeping. Adjunctive hypnotics may be required. Finally, there is a small risk of orthostatic hypotension with the drug.

Selegiline transdermal patch has received an approvable letter from the FDA, and at the time of this writing final approval was pending.

Aprepitant (MK-869)

Substance P binds to the neurokinin-1 receptor (NK-1) in brain. NK-1 receptors are distributed across regions that contain norepinephrine and 5-HT neurons. In lower animals, substance P activation has been associated with stress responses (73). Mice in which NK-1 receptors have been genetically knocked out appear less anxious (74), as do animals given an NK-1 antagonist (75). These data suggest that NK-1 antagonists may be helpful in disorders viewed as untoward stress responses, such as anxiety and depression.

Aprepitant (MK-869)—a Merck Laboratories substance P antagonist—was reported to be significantly more effective than placebo (and comparable to paroxetine) in reducing depression (73). A second substance P antagonist was also reported to separate from placebo in melancholic depressives (76). The manufacturer of both pursued a new formulation of MK-869, which failed to separate from placebo in five double-blind antidepressant trials (77). In three of the trials, the active comparator paroxetine did separate from placebo. Merck has halted this development program, although other companies may still be pursuing this drug class as an antidepressant.

The drug has relatively little in the way of side effects and was well tolerated. In a different dosage, aprepitant is available for limited acute use (e.g., for 2 days around administration of chemotherapy) to prevent cisplatin-induced nausea and vomiting.

Gepirone

Gepirone is a 5-HT_1A agonist that has been under study for many years as an immediate-release formulation. Most recently, one manufacturer (Organon) was attempting to develop a long-acting formulation of the drug as an antidepressant. In one report, the drug separated from placebo on Hamilton Depression Rating Scale change scores from baseline to weeks 3 and 8 (78). In another analysis, the effects appeared to be more pronounced on symptoms of anxiety, which is consistent with previous observations (79). Side effects are generally mild and include dizziness, nausea, and insomnia. However, the file submitted to the FDA was not strong enough to win approval.

Mifepristone

Mifepristone is an antagonist for the low-affinity glucocorticoid receptor as well as a progesterone antagonist. Two decades ago my colleagues and I hypothesized that the delusions of psychotic depression and similar states were due to excessive cortisol activity (80). Clinical data suggested that at doses of 600 mg/day for 4—7 days, mifepristone may improve the psychotic symptoms of delusional depression (81), and two recent double-blind studies support this observation (82, 83). Mifepristone is currently in Phase III trials. The drug’s side effect profile appears relatively benign; rashes are seen in 4%—10% of patients.

Corticotropin-releasing hormone antagonists

Several pharmaceutical companies are developing corticotropin-releasing hormone (CRH) antagonists. CRH in the brain is involved in initiating stress responses. CRH is found in the hypothalamus, amygdala, and cortex. One CRH antagonist—R121919—has been reported in an open-label German study to reduce depressive symptoms in hospitalized MDE patients (84). However, the drug’s development was discontinued because of laboratory test abnormalities. This remains an area of active drug development.

Olanzapine-fluoxetine combination

The combination of olanzapine and fluoxetine has been reported to promote antidepressant responses in nonresponding depressed patients (85). The mechanism has been thought to reflect mobilization of prefrontal dopamine and norepinephrine (86). This strategy has been under further study. Thus far, the data suggest that atypical antipsychotics rapidly convert nonresponders to responders by 1 week but may not offer any advantage at 8 weeks.

A combination product of olanzapine and fluoxetine has been approved for the treatment of bipolar I depression. In the pivotal trials, both olanzapine and the combination of olanzapine and fluoxetine separated from placebo (87). The combination has also been studied in psychotic or delusional depression, where it was more effective than placebo in one of two pivotal studies (88). An analysis of the combined data indicated that the combination, but not olanzapine alone, separated from placebo. However, separation from placebo occurred only after 4 weeks. At this point it is not anticipated that the combination will be developed further for delusional depression.

Pharmacogenetics

Pharmacogenetics is becoming a major focus in psychopharmacologic research. This approach uses genetic alterations—often single-nucleotide polymorphisms (SNPs)—to assess the likelihood of response to a particular drug or class of drugs or to predict side effects. The approach has been used in various psychiatric disorders, with perhaps the strongest findings seen in depression. Findings are summarized in Table 3.

Several years ago the Milan group reported that a short form of the serotonin transporter was associated with poor responses to specific paroxetine (89, 90). In contrast, the alternate long form predicted positive responses. This observation has been confirmed in other studies with Caucasians (91), but the opposite prediction pattern has been reported in studies with Asian populations (92). Recently our group reported that the long form of the transporter was only a mild predictor of positive response to paroxetine in geriatric patients (93). In contrast, the short form of the transporter predicted intolerance to the SSRI paroxetine but not to the 5-HT₂ antagonist mirtazapine. Patients who were s/s tolerated mirtazapine much better than did l/l patients (93). Our view of previous studies has been that using last-observation-carried-forward (LOCF) approaches to analysis of patients who dropped out may have resulted in a confusion of intolerance and nonresponse in s/s patients. At any rate, the data do suggest that in Caucasians the SSRI response may not be optimal.

The 102 T/C SNP of the 5-HT_2A receptor has been associated with the response pattern to clozapine (94) in patients with schizophrenia. We explored whether the C/C homozygote for the receptor—seen in some 25% of the population—was associated with response to either paroxetine or mirtazapine in geriatric depressives (95). The C/C homozygocity predicted intolerance to paroxetine, with over 40% dropping out because of adverse events by 8 weeks. In contrast, the C/C form did not predict intolerance to mirtazapine. Response or remission to either drug was not predicted by the 5-HT_2A variants. The s/s form of the transporter and the C/C form of the 5-HT_2A receptor independently predicted intolerance to paroxetine (93). Thus, these data suggest that alterations in 5-HT reuptake or 5-HT_2A postsynaptic receptor activity affect the ability to tolerate an SSRI but do not adversely affect tolerability of a postsynaptic receptor antagonist.

Similarly, allelic variation of the norepinephrine transporter has been explored as a predictor of response to the selective norepinephrine reuptake inhibitor milnacipran in Japanese depressives (96). The T allele of the T-182C polymorphism of the norepinephrine transporter predicted positive response to the drug; the A/A form did not. Allelic variation for the serotonin transporter did not predict response to the norepinephrine agent.

Apolipoprotein E ε4 (APOE-4) has been reported to be a risk factor for Alzheimer’s disease. Individuals with this allele may be at increased risk of greater morbidity after surgery or after head injury and have an increased risk of obstructive sleep apnea. In our geriatric study (97, 98), we explored the hypothesis that APOE-4 alleles were predictors of poor overall response to antidepressant therapy in geriatric patients. This prediction was not borne out, but patients with APOE-4 al-leles were dramatic responders to mirtazapine but not to paroxetine (98). The explanation is not entirely clear, but APOE status may be associated with noradrenergic dysfunction (99) or excessive cortisol activity (100), both of which are targets for mirtazapine therapy (100, 101).

Glucocorticoid receptors are nuclear and are surrounded by chaperone heat-shock proteins. As discussed above, alterations in one HSP have been reported to be associated with multiple depressive episodes and rapid response to drug therapy (20). These alterations may affect the individual’s ability to halt the stress response. Mirtazapine was frequently used in this study, and the prediction of rapid response may have to do with the drug’s ability to lower cortisol levels (101). Further studies in other subject populations will help elucidate this issue.

In regard to pharmacokinetics, two major systems have been the focus of much recent research: P450 2D6 in the liver and medication-resistant P-glycoprotein (mr-P-GP), which controls efflux of drug from the brain. P450 represents a basket of enzymes found primarily in the liver that metabolize various drugs. The best known is P450 2D6. Many drugs serve as substrates as well as inhibitors of P450 2D6, whereas some stimulate activity. There are numerous alleles for 2D6; some connote increased clearance or metabolism, whereas others connote slow metabolism. Slow metabolizers should be more likely to experience side effects. Rapid or ultrafast metabolizers may clear the drug so quickly that they fail to achieve adequate blood levels and are thus less likely to attain a drug effect.

We explored whether slow metabolizers in a geriatric population were more likely to drop out because of side effects of paroxetine (a substrate and inhibitor of 2D6) or of mirtazapine (a substrate but not an inhibitor) (93, 97). We did not observe an effect of 2D6 alleles on dropouts due to adverse events from either drug, although the number of very slow metabolizers (i.e., null alleles) was small. As indicated above, we did observe pharmacodynamic predictors of SSRI response in this study (97).

In the past few years greater attention has been given to mr-P-GP as a predictor of antidepressant response. In mice, knocking out the gene for the pump protein points to its role in facilitating the efflux of both cortisol and antidepressants from the brain (102—105). In studies to date using knockouts, citalopram, amitriptyline, and trimipramine appear to be transported out of mouse brain by P-GP (103—104). Alterations in this gene may tell us more about treatment resistance than does drug clearance via the liver. However, the significance of these observations on P-GP in lower animals to the treatment of depressed patients is unclear, since the knockout model may not be fully relevant to the clinic. Still, this is an interesting area that is fast becoming a focus of pharmacokinetic research.

Summary

Recent studies point to key brain areas as having important roles in depression as well as to specific genes as risk factors for developing depression, often in interaction with environmental stress. New antidepressant strategies are being pursued, and despite some recent disappointments in this area, pharmacogenetics is pointing to potential tools for selecting drugs or deciding how to dose them.

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Table 1. Hippocampal Volume in Major Depression

1.	Several studies demonstrate smaller hippocampal volumes in patients with major depression (+28—+33)
2.	Others show no differences between patients with major depression and control subjects (+34—+37)
3.	If the amygdala is included in volume analysis, hippocampal volume may not measure smaller in depressed subjects (+38)
4.	Duration of depression may be (+39) or may not be (+31) associated with smaller hippocampal volume
5.	Early abuse may be associated with smaller hippocampal volume in subjects with major depression (+32)
6.	Hippocampal size is strongly influenced by genetics (+42—+45)
7.	Small hippocampal volume may be a risk factor for major depression or posttraumatic stress disorder (+31, +44)

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Table 2. New Psychopharmacological Agents

Agent	Principal Mechanism of Action	Possible Indications	Status in United States
Duloxetine	Norepinephrine/serotonin reuptake blocker	Major depression Diabetic neuropathic pain Stress urinary incontinence	Approved for major depression and diabetic neuropathic pain; pending approval for incontinence
Selegiline (transdermal patch)	MAO A and B inhibitor in brain	Major depression Atypical depression ADHD	Approval letter for major depression only Not under study
Aprepitant	NK-1 or substance P antagonist	Major depression Cisplatin-induced nausea and vomiting	Development halted for major depression due to lack of efficacy Approved for cisplatin-induced nausea and vomiting
Gepirone	5-HT_1a agonist	Major depression Generalized anxiety disorder	Nonapprovable letter for major depression
Mifepristone	Clucocorticoid receptor antagonist Alzheimer’s disease (early)	Psychotic symptoms in psychotic major depression Phase II for Alzheimer’s disease	Phase III for psychotic depression
R121919	CRH antagonist	Major depression Anxiety disorders	Development dropped due to liver toxicity
Olanzapine-fluoxetine combination	Atypical antipsychotic (dopamine/serotonin) antagonist; serotonin reuptake blocker; prefrontal cortex release of norepinephrine and dopamine	Bipolar I depression Psychotic major depression Refractory depression	Approved for bipolar I depression One positive trial in psychotic major depression with no further studiesunder way Phase III program for refractory depression
MAO=monoamine oxidase inhibitor; ADHD=attention deficit hyperactivity disorder; NK-1=neurokinin-1 receptor; CRH=corticotropin-releasing hormone

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Table 3. Pharmacogenetic Findings in Major Depression

Allele/Gene	Findings
s/s form of 5-HT transporter	s/s predicts poor response to SSRIs in Caucasians (+89—+91)
	s/s predicts intolerance to SSRIs (+93)
	l/l predicts poor response to SSRIs in Asians (+92)
	s/s predicts tolerability with mirtazapine (+93)
102 R/C allele for 5-HT_2c receptor	C/C predicts intolerance to paroxetine but not to mirtazapine (+95)
182 T/C allele for norepinephrine transporter	T allele predicts poor response to milnacipran in Japanese (+96)
APOE-4	APOE-4 patients are rapid responders to mirtazapine but not to paroxetine (+98)
rS1360780 gene for FKBPS (chaperone heat shock protein)	T/T homozygotes demonstrate rapid response to a number of antidepressants, particularly mirtazapine and citalopram (+20)
P450 2D6	In geriatric depression, alleles representing intermediate and slow metabolizers do not predict higher dropout rates due to adverse events of paroxetine or mirtazapine; study included few patients with null alleles (+95)

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Table 1. Hippocampal Volume in Major Depression

1.	Several studies demonstrate smaller hippocampal volumes in patients with major depression (+28—+33)
2.	Others show no differences between patients with major depression and control subjects (+34—+37)
3.	If the amygdala is included in volume analysis, hippocampal volume may not measure smaller in depressed subjects (+38)
4.	Duration of depression may be (+39) or may not be (+31) associated with smaller hippocampal volume
5.	Early abuse may be associated with smaller hippocampal volume in subjects with major depression (+32)
6.	Hippocampal size is strongly influenced by genetics (+42—+45)
7.	Small hippocampal volume may be a risk factor for major depression or posttraumatic stress disorder (+31, +44)

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Table 2. New Psychopharmacological Agents

Agent	Principal Mechanism of Action	Possible Indications	Status in United States
Duloxetine	Norepinephrine/serotonin reuptake blocker	Major depression Diabetic neuropathic pain Stress urinary incontinence	Approved for major depression and diabetic neuropathic pain; pending approval for incontinence
Selegiline (transdermal patch)	MAO A and B inhibitor in brain	Major depression Atypical depression ADHD	Approval letter for major depression only Not under study
Aprepitant	NK-1 or substance P antagonist	Major depression Cisplatin-induced nausea and vomiting	Development halted for major depression due to lack of efficacy Approved for cisplatin-induced nausea and vomiting
Gepirone	5-HT_1a agonist	Major depression Generalized anxiety disorder	Nonapprovable letter for major depression
Mifepristone	Clucocorticoid receptor antagonist Alzheimer’s disease (early)	Psychotic symptoms in psychotic major depression Phase II for Alzheimer’s disease	Phase III for psychotic depression
R121919	CRH antagonist	Major depression Anxiety disorders	Development dropped due to liver toxicity
Olanzapine-fluoxetine combination	Atypical antipsychotic (dopamine/serotonin) antagonist; serotonin reuptake blocker; prefrontal cortex release of norepinephrine and dopamine	Bipolar I depression Psychotic major depression Refractory depression	Approved for bipolar I depression One positive trial in psychotic major depression with no further studiesunder way Phase III program for refractory depression
MAO=monoamine oxidase inhibitor; ADHD=attention deficit hyperactivity disorder; NK-1=neurokinin-1 receptor; CRH=corticotropin-releasing hormone

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Table 3. Pharmacogenetic Findings in Major Depression

Allele/Gene	Findings
s/s form of 5-HT transporter	s/s predicts poor response to SSRIs in Caucasians (+89—+91)
	s/s predicts intolerance to SSRIs (+93)
	l/l predicts poor response to SSRIs in Asians (+92)
	s/s predicts tolerability with mirtazapine (+93)
102 R/C allele for 5-HT_2c receptor	C/C predicts intolerance to paroxetine but not to mirtazapine (+95)
182 T/C allele for norepinephrine transporter	T allele predicts poor response to milnacipran in Japanese (+96)
APOE-4	APOE-4 patients are rapid responders to mirtazapine but not to paroxetine (+98)
rS1360780 gene for FKBPS (chaperone heat shock protein)	T/T homozygotes demonstrate rapid response to a number of antidepressants, particularly mirtazapine and citalopram (+20)
P450 2D6	In geriatric depression, alleles representing intermediate and slow metabolizers do not predict higher dropout rates due to adverse events of paroxetine or mirtazapine; study included few patients with null alleles (+95)