James G. Barbee, MD

Approximately 32 to 35 million adults in the United States have an episode of major depression sometime during their lifetime, and many of them do not respond to initial treatment.

 The results of an analysis undertaken by Fava and Davidson

 suggest that between 29% and 46% of depressed patients fail to respond fully to antidepressant treatment of adequate dose and duration; about 15% of patients fail to respond to multiple treatment trials.

 have suggested that patients with treatment-resistant depression (TRD) may represent a biologically unique subtype of depressed patients. Unfortunately, the chances for full recovery diminish the longer a patient remains depressed-a fact that lends a sense of urgency for appropriate therapy.

Before discussing the effectiveness of individual agents in TRD, it is important to review recent evidence regarding the principles of using these agents to maximize the chance of a response.

 Some of the most salient findings from the STAR*D trial on this topic are summarized in 

The standard strategy for managing patients who are depressed includes an adequate clinical trial; when the response is unsatisfactory, the clinician’s options are:

• Combine a second antidepressant with the first

• Add a second drug that is not approved as an antidepressant

Antidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.

 When examining switching studies, be certain that the reason for switching was a failure to respond to an adequate antidepressant trial rather than a lack of tolerability, as these are fundamentally different issues.

The concept of switching classes of antidepressants is only as valid as the theoretical basis by which the antidepressants are grouped. As noted, some treatment guidelines allow 2 SSRI trials before switching classes. For example, in a study by Thase and colleagues,

a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not. It is hoped that as our knowledge of the mechanism of action of antidepressants grows more sophisticated, methods of classifying these agents will evolve to better guide clinicians in switching and combination strategies.

The clinical trial data on switching are surprisingly sparse-a recent meta-analysis identified only 4 randomized controlled trials.

 These trials include data from level 2 of the STAR*D study in which patients who were switched from citalopram to sertraline, venlafaxine XR, or bupropion SR showed remission rates of 27%, 25%, and 26% (respectively) based on the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16).

 The meta-analysis found a modest but statistically significant advantage in switching from SSRIs to non-SSRIs. Of the 5 comparisons, 3 used venlafaxine, which is predominately a serotonergic agent (the serotonin-norepinephrine Ki ratio is 30), although it is classified as an SNRI. This may account for the relative lack of separation. One wonders if duloxetine, with a Ki ratio of 9 and relatively greater noradrenergic potency, might show greater separation.

 However, only one open-label switching study with duloxetine has been published to date.

In switching antidepressants, 2 pharmacokinetic issues are important:

• Drugs with potent cytochrome P-450 (CYP450) effects-particularly fluoxetine (because of its long half-life)-may produce toxic levels of medications taken concurrently, such as TCAs that are also metabolized by these systems. (This effect is even more of an issue with combinations.)

• Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.

What we need are agents with novel mechanisms of action. As indicated in 

, there is a rich pipeline of candidates. Some of these agents, such as agomelatine, are relatively far along in the clinical trial process with human subjects. Others, such as amibegron and sipatrigine, have been shown to be efficacious only in animal models of depression and their benefit is therefore highly speculative.

Some of the drugs have been tried as augmentation agents as well (eg, riluzole). Agents such as pramipexole, memantine, riluzole, and ketoconazole are already available in the United States.

Proposed mechanisms of action vary widely, but 2 development strategies are generating a great deal of activity:

• Agents are being developed that affect corticosteroid function at various levels. (Glucocorticoids have figured prominently in recent theories as major agents in stress-induced neuronal injury and cell death leading to depression.

• Compounds are being developed that induce the synthesis of brain-derived neurotrophic factor (BDNF), particularly through their effects on glutamate receptors.

In a sense, these 2 strategies are related: it has been proposed that BDNF acts as a modulator of neuronal repair and even neurogenesis in response to cortisol-induced brain injury. The findings with ketamine are particularly exciting. A recent study reported that ketamine, through its activity as an 

-methyl-D-aspartate (NMDA)-receptor antagonist, increases synaptic glutamate and therefore stimulates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (both NMDA and AMPA receptors are subtypes of glutamate receptors).

 AMPA potentiators are known to induce BDNF production more rapidly than current antidepressants.

It has been hypothesized that a more rapid induction of BDNF would lead to a faster onset of antidepressant action. In a study by Zarate and colleagues,

 the onset of the antidepressant effect of ketamine occurred within 2 hours. Unfortunately, the drug must be given by intravenous infusion, but because the effect persisted for 7 days, ketamine treatment may be useful if given as a series.

Another NMDA-receptor antagonist now available in the United States is memantine (FDA-approved for Alzheimer disease). Memantine was shown to be effective in an open-label study in major depression. In a double-blind, randomized trial it showed comparable effects to escitalopram in patients with major depression and alcohol dependence.

 However memantine failed to separate from placebo in a double-blind, placebo-controlled study in major depression.

 The less robust antidepressant properties of memantine when compared with those of ketamine may be due to differing NMDA receptor binding properties between the 2 compounds.

In this category there are 2 similar strategies: (1) combination, that is, combining 2 FDA-approved antidepressants with presumably complementary mechanisms of action; and (2) augmentation, in which a drug not approved as an antidepressant is used with an FDA-approved antidepressant. Such pairings can be used either at the beginning of therapy to speed the response (an accelerator strategy) or to improve the overall response, thereby enhancing the odds of achieving remission. As noted, when combining agents, one must be aware of possible CYP450-based pharmocokinetic interactions or other pharmacological interactions, such as the risk of serotonin syndrome when an SSRI is combined with an MAOI.

 Of the 2 strategies, the addition of a second antidepressant is the more intuitively obvious. Randomized controlled trials have supported the superior efficacy of a TCA/SSRI combination, as well as a mirtazapine/SSRI combination; open studies have done the same for TCA/MAOI and SSRI/bupropion combinations.

 A positive retrospective chart review of 10 patients treated with a combination of duloxetine and bupropion has also been published.

These findings raise the question of whether combining antidepressants is superior to switching. For example, an open-label, nonrandomized study by Lam and colleagues

 found that when 61 patients who were taking citalopram or bupropion SR for TRD were either switched to the other drug or given the combination, the combination group showed statistically greater rates of response and remission. At a minimum, combination treatments ensure that a partial response to the first agent will not be lost.

If the switching and combination literature is conspicuous by its paucity, the augmentation literature is abundant-but the quality of evidence varies tremendously and the reader must maintain a “buyer beware” approach. One recent review concluded that although studies of augmentation were abundant, many were underpowered and uncontrolled.

Several comprehensive reviews have been published.

Evaluation strategies have been suggested to assess the quality of evidence.

 In general, augmentation strategies are recommended in the event of a partial response to an antidepressant. Switching is preferred in the event of a nonresponse.

 One of the few studies to examine this issue systematically found numerically higher response rates among partial responders compared with nonresponders when lithium or desipramine was added to fluoxetine, but these differences were not statistically significant.

 presents a summary of agents that may be effective. Although the amount and quality of evidence about the agents in category A is meaningful, the differentiation of groups B and C is somewhat arbitrary.

The presumed mechanism of action of augmentation agents varies tremendously and is generally believed to complement the action of the primary antidepressant in some predictable theoretical manner. Questions remain about the validity of our current classification systems for grouping augmentation agents-an issue of crucial importance for clinicians who need to pair them with antidepressants for maximum benefit.

Lithium, the classic augmentation agent, has been the subject of the greatest number of studies. A recent meta-analysis identified 10 randomized, placebo-controlled trials, all of which were relatively small (the largest included 61 subjects).

 The authors of these studies concluded that lithium was significantly more effective than placebo. The vast majority of the studies with lithium did not include SSRIs but instead used TCAs. Remission rates from level 3 of the STAR*D trial using lithium as an augmentation agent with citalopram were only 13.2% (measured by QIDS-SR), whereas T

 augmentation remission rates at this same step were 24.7%.

 Although these differences were not statistically different, there was a significantly higher dropout rate in the lithium group.

As with lithium, a recent review concluded that the trial data that support the efficacy of T

 augmentation are of better quality with TCAs than with SSRIs.

 Although it has been reported that approximately 50% of patients with unipolar depression given thyroid augmentation show a response, a pooled analysis of 4 randomized double-blind studies of T

 augmentation revealed nonsignificant effects, but the results of 1 of the 4 studies may have accounted for this finding.

By contrast to these relatively small studies with classical augmentation agents, there are a number of large, randomized, placebo-controlled trials of atypical antipsychotics in nonpsychotic, unipolar depression in combination with antidepressants. These studies culminated in the first-ever FDA approval of an agent specifically for antidepressant augmentation-aripiprazole. In their meta-analysis, Papakostas and colleagues

 conclude that the results support the utility of atypical augmentation, even in the absence of double-blind, placebo-controlled trials with aripiprazole (now available) and ziprasidone. Virtually all of the studies to date of atypical augmentation have been conducted with SSRIs, although there are reports that aripiprazole was effective with bupropion, tranylcypromine, and mirtazapine.

The study of tranylcypromine (an MAOI) with aripiprazole suggests the need for cautious use of some combinations. As noted in the package insert, tranylcypromine should not be coadministered with dibenzazepine-related entities because of the risk of severe interactions, including hypertensive crises and seizures.

 Some of the atypical antipsychotics (eg, aripiprazole, ziprasidone) have a high affinity at the 5-HT

-receptor; agents such as buspirone, which also binds at this receptor site, are not recommended for use with MAOIs. Ziprasidone also has a similar potency to imipramine in terms of blocking norepinephrine and serotonin reuptake (imipramine is al-so relatively contraindicated with MAOIs).

 There is a report of 5 patients treated safely with risperidone and MAOIs, and another of 12 patients exposed to olanzapine with the selegiline patch.

In general, the effective dosage of atypical antipsychotics in this role seems to be lower than that used in psychosis. Data on the long-term risks in depressed patients, including tardive dyskinesia and metabolic syndrome, are urgently needed. The recent FDA approval of quetiapine as monotherapy in bipolar depression raises questions as to whether some of the atypical antipsychotics may be effective (and perhaps better tolerated) when given as a single agent for unipolar TRD.

In regard to the value of switching atypicals, if one agent fails, is it worth attempting trials of another? There are limited data that show that switching to another atypical is worthwhile.

However, results from randomized controlled trials are still needed.

 may be most effective when used for augmentation purposes. The quality of the evidence varies widely, particularly in the second and third categories of the table. For example, in a pooled analysis, estrogen was effective when added to sertraline in a group of depressed women over 60 years; however, the total sample size was only 127.

 There are small, positive, double-blind studies for agents such as testosterone, L-tryptophan, and omega-3-fatty acids.

In the case of pindolol, there are negative studies as well, and in a recent review, the evidence supporting its efficacy was rated as a “C” (the lowest rating).

Open-label reports for buspirone were positive, but 2 randomized controlled trials were negative.

Buspirone was used as an augmentation agent for citalopram in level 2 of STAR*D: remission rates were 33% by the QIDS-SR compared to 39% with bupropion at the same stage. Although the remission rates between the 2 drugs did not differ significantly, the bupropion group had a significantly greater reduction in depression scores.

Despite reports that suggest the efficacy of lamotrigine, this agent did not separate significantly from placebo in the only large, multicenter, double-blind, placebo-controlled trial to date.

 Modafinil, used in 2 randomized, placebo-controlled trials did not show significant placebo separation on most mood-scale scores, but it did reduce sleepiness and fatigue.

The unfortunate reality is that conducting large, double-blind, placebo-controlled trials is extremely expensive and time consuming. Definitive evidence of the efficacy of these agents is likely to accrue slowly. Negative studies may not prove that a drug is ineffective because of factors such as high placebo response rates, or the more subtle reality that there may be meaningful subgroups of patients with TRD that we are currently unable to identify.

Agomelatine (Valdoxan, Melitor)
Amantadine (Symmetrel)
Amibegron
Aminoglutethimide (Cytadren)
Aripiprazole (Abilify)
Atomoxetine (Strattera)
Bromocriptine (Parlodel)
Bupropion (Wellbutrin, Zyban)
Bupropion SR (Wellbutrin SR)
Buspirone (BuSpar)
Carbamazepine (Carbatrol, Tegretol, others)
Celecoxib (Celebrex)
Citalopram (Celexa)
Dehydroepiandrosterone
Desipramine (Norpramin; Pertofrane)
Dexamethasone (Decadron, others)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Folic acid (Folacin, Folate, Pteroylglutamic acid, Vitamin B9)
Gabapentin (Neurontin)
Imipramine (Tofranil)
Inositol
Ketamine
Ketoconazole (Nizoral)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
L-tryptophan
Melatonin (Bevitamel)
Memantine (Namenda)
Metyrapone (Metopirone)
Mifepristone (Mifeprex)
Mirtazapine (Remeron)
Modafinil (Provigil)
Nefazodone (Serzone)
Olanzapine (Zyprexa)
Omega-3-acid ethyl esters (Lovaza)
Paroxetine (Paxil)
Pergolide (Permax)
Pindolol (Visken)
Pramipexole
Quetiapine (Seroquel)
Riluzole
Risperidone (Risperdal)
Ropinorole (Requip)
S-adenosyl-l-methionine (SAMe)
Selegiline (Emsam, Atrapryl, Carbex, others)
Sertraline (Zoloft)
Sipatrigine
Topiramate (Topamax)
Tranylcypromine (Parnate)
Trazodone (Desyrel)
Valproate/valproic acid (Depakote, others)
Venlafaxine (Effexor)
Yohimbine (Procomil)
Ziprasidone (Geodon)

 Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder. results from the National Comorbidity Survey replication (NCS-R). 

 Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 

 Berlim MT, Turecki G. Definition, assessment and staging of treatment-resistant refractory major depression: a review of current concepts and methods. 

 Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? 

 Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depression disorder: analysis with the life table and regression models. 

 Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. 

 Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. 

 Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive disorders IV. Medications and other biological treatments. 

 American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder (revision). 

 Thase ME, Feighner JP, Lydiard RB. Citalopram treatment of fluoxetine nonresponders. 

 Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: A meta-analysis comparing within- versus across-class switches. 

 Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. 

 Koch S, Hemrick-Luecke SK, Thompson LK, et al. Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats. 

 Karp JF, Whyte EM, Lenze EJ, et al. Rescue pharmacotherapy with duloxetine for selective serotonin reuptake inhibitor nonresponders in late-life depression: outcome and tolerability. 

 Norman TR, Burrows GD. Emerging treatments for major depression. 

 Overstreet DH, Stemmelin J, Griebel G. Confirmation of antidepressant potential of the selective b3 adrenoreceptor agonist amibegron in an animal model of depression. 

 Tsai SJ. Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. 

 Krishnan V, Nestler EJ. The molecular neurobiology of depression. 

 Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ke-tamine: role of a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors. 

 Skolnick P. AMPA receptors: a target for novel antidepressants? 

 Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an 

-methyl-d-aspartate antagonist in treatment-resistant major depression. 

 Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantine in major depressive disorder. 

 Muhonen LH, LÃ¶nngvist J, Juva K, Alho H. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. 

 Zarate CA, Singh JB, Quiroz JA, et al. A double-blind placebo-controlled study of memantine in the treatment of major depression. 

 Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resis-tant/refractory major depression: an overview. 

Barowsky J, Schwartz TL. Part 1: An evidence-based approach to augmentation and combination strategies for treatment-resistant depression. 

 2006;3:42-61.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. 

Articles

The chances for full recovery from major depressive disorder diminish the longer a patient remains depressed-a fact that lends a sense of urgency for appropriate therapy.

Treatment-Resistant Depression

The management of treatment-resistant depression (TRD) remains a vexing clinical problem for a large population of patients and their clinicians. An estimated 32 to 35 million adults in the United States experience an episode of major depression during their lifetime.

 When depressed patients present for treatment, the results are often less than satisfactory. Even under the relatively ideal treatment conditions of the recent NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 32.9% of patients achieved remission in level 1 with citalopram.

 An analysis of 36 open and double-blind antidepressant trials found a 36% rate of partial response or nonresponse.

 About 15% of patients had depression that failed to respond to multiple treatment trials.

 Depressed patients report impaired function and they overuse medical services.



 Patients with TRD may represent a biologically unique subtype of depressed persons.

 Unfortunately, the longer a patient remains depressed, the lower his or her chance of recovery-a fact that lends a sense of urgency to finding appropriate therapy.



 This article focuses on recent innovations in diagnostic issues, tactics, and strategy, and takes a brief look at the future.





 The lack of consensus about how to define treatment resistance and how it should be classified are major methodological problems.

 The term “treatment resistance” obviously implies an inadequate response to antidepressant therapy. Sackheim

 notes that 4 of the following conditions must be met before the adequacy of an antidepressant trial can be judged:

Drug dosage was titrated to the maximum when appropriate.

The drug was administrated for an adequate duration and at maximal dosage as appropriate.

The adequacy of patient adherence to therapy was monitored.

The degree of nonresponse (partial vs complete) was recorded.

Without such detail, one cannot be certain that patients are not pseudo- resistant (ie, inappropriately classified as having TRD, when the real issue is suboptimal treatment). Up to half of treatment nonresponse may be a result of  poor adherence to medication regimens and/or poor tolerability.



 What constitutes an adequate clinical trial? In general, 6- to 8-week trials are recommended, with 2 to 4 weeks of medication at the upper end of the standard dosage.

 However, one of the most important findings of STAR*D was that many patients required longer than 8 weeks to respond, and thus an adequate trial may be 12 weeks or longer.

 Minimum target dosages for an adequate duration have been recommended.

 Some data suggest that without some clinical improvement after 2 to 4 weeks, the odds of a response are greatly diminished.

 a patient is not considered to have TRD until he or she experiences a poor response to at least one adequate clinical trial. Berlim and Turecki

 concluded that there is a “general sense” that the definition of treatment resistance requires the failure of 2 adequate trials of antidepressants from different classes. These researchers note, however, that there is little validation that patients who experience 2 failed trials with an antidepressant from the same class are less resistant that those who fail to respond to different classes.

 Beyond the general issue of treatment resistance, attempts have been made to classify the degree of treatment resistance. Factors such as the number of antidepressant drug classes used, the trial duration, and the response to electroconvulsive therapy have been included. Berlim and Turecki

 have recently published a review of 3 of the most widely used staging methods.

 From my perspective, the most useful definition of TRD for a clinician is simple: it is the failure to achieve a response to a medication to any degree short of remission. Any response short of remission is associated with impairment and an increased risk of relapse and should therefore trigger some kind of treatment intervention. It is important for clinicians to be aware of the research issues regarding the classification of resistance so that they may properly evaluate the results of clinical trial data, particularly when comparing one study with another. More specifically, the greater the degree of treatment resistance in a patient population, the more difficult it becomes to demonstrate a response to any agent.



 Obviously, one must consider the wide variety of possible medical causes of depression that 

require proper diagnosis to determine an appropriate intervention (Table). However, patients with TRD have high rates of comorbid psychiatric disorders as well; 35% of the depressed patients in STAR*D had at least 1 additional Axis I disorder.

 The most important assessment considerations include comorbid anxiety disorders, pain, insomnia, drug abuse, bipolar II disorder, attention deficit disorder, and partial response.

 Of the 2876 patients with major depression in STAR*D who were eligible for analysis, the rates of comorbid anxiety disorders ranged from 12% (agoraphobia) to 31% (social anxiety); 53% of the patients qualified for anxious depression (major depression with high levels of anxiety symptoms).

 Patients with anxious depression and a variety of concurrent anxiety disorders had significantly lower remission rates.

 There was a relatively linear decline in remission rates with increasing anxiety symptom scores in patients with anxious depression; these persons also had relatively worse adverse effects and more serious adverse events with medication.

 Comorbid social anxiety disorder, in particular, has been associated with a more malignant course of depression.



 Pain symptoms are common in depressed persons and are among the symptoms least relieved by treatment.

 The likelihood of a poor response to antidepressants increases with increased pain severity. A greater than 50% reduction in pain symptoms early on improved the chance of remission in depressed patients treated with duloxetine.



 Insomnia, a problem often seen in this patient population, is a risk factor for depression, and should be aggressively treated.

 A recent double-blind, clinical trial found that the addition of a hypnotic (eszopiclone) to fluoxetine therapy lead to significantly higher response and remission rates at the end of the study than did the addition of placebo.



 Almost 30% of patients with major depression in the STAR*D also abused alcohol and/or drugs.

 Another large sample found that those with comorbid depression and alcohol abuse were significantly younger at the onset of their first depressive episode, first psychiatric hospitalization, and first suicide attempt than were depressed persons who did not abuse alcohol.

 This comorbidity also led to a greater number of depressive episodes and suicide attempts. 

 In the STAR*D study there was a strong trend toward lower rates of remission in response to citalopram as measured by the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) rating scale. This trend approached, but did not quite reach, statistical significance by the QIDS-SR definition.



 What seasoned clinician has not worked with a chronically depressed patient who manifests symptoms of hypomania or reports such episodes for the first time after months or years of treatment? Findings from a long-term prospective study indicate that depressive symptoms were present during 50% of the weeks of follow-up in a sample of 86 patients with bipolar II disorder; such symptoms were by far the most predominant.

 The diagnosis of bipolar II disorder can be difficult to make and, as a result, bipolar disorder is still often missed.

 The role of antidepressants (particularly as monotherapy) is especially controversial in bipolar II disorder, because of concerns about antidepressant-induced mania or hypomania.



 Estimates of the prevalence of comorbid depressive disorders in first-rate studies of children with ADHD have ranged from 9% to 38%, and elevated rates of major depression in adults with ADHD have been reported as well.

 Adults with major depression and ADHD were more likely to present for treatment than those with ADHD alone.



 In recent years, there has been growing recognition that getting better is not good enough. In treating depression, the goal is to become well, (ie, remission). Partial responders remain significantly functionally impaired, and an increased risk of relapse of depression among these patients has been shown in STAR*D as well as other studies.



 We need to better understand the mechanism of action of antidepressants. This knowledge will help guide clinicians as they switch and/or combine agents. It is hoped that improved methods of classifying patients will be developed to improve the success rates of treatments. Improved study designs (such as that used in the aripiprazole trials in which the placebo was given on a single-blind basis to patients from the beginning of the study) may help minimize the placebo response.



 In addition to the need for novel compounds with new mechanisms of action (as well as a better understanding of the ones we have), a major innovation will be to move from the paradigm of average response to one of personalized medicine. Average response refers to the current practice of treating depression based on evidence that a drug benefits a large population. For example, if compound X is shown to be effective in 60% of individuals with major depression, all patients with major depression are therefore considered to be candidates for treatment with the drug. This often turns out to be a time-consuming and inefficient process.

 Personalized medicine would use the results from genetic analysis or other testing methods (such as frontal quantitative electroencephalography) to predict an individual’s response to individual antidepressant agents.

 Some of the most provocative studies thus far have involved gene-based variations in the CYP450 system, particularly CYP 2D6.

 However, recent genetic data, much of it from the STAR*D study, have been analyzed to show associations between specific genetic variations and both treatment response and adverse events. Thus, variations in the genes encoding the 5HT2A receptor, GRIK4 (a subtype of glutamate receptor), and the ABCB1 transporter (a gene involved in encoding transporters across the blood-brain barrier) have shown associations with antidepressant response.

 Variations in the serotonin transporter gene solute carrier family 6, member 4 (SLC6A4) promoter were associated with citalopram-induced side effects.

 Markers within GRIK2 and GRIA3 (other genes encoding glutamate receptors) were significantly associated with the emergence of suicidal ideation with citalopram in STAR*D.



 Such findings raise the hope not only of more precise selection of antidepressant treatments and a better ability to predict tolerability but also offer new targets for antidepressant drug development. Given the heterogeneity of the molecular targets that have already been identified, it is little wonder that the proper diagnosis and management of TRD is such a complex and sometimes frustrating endeavor for both the patient and the clinician-but so fulfilling when one is successful.

Outcome Assessment in Depression, by Waguih William IsHak, MD

The Cognitive Behavioral Analysis System of Psychotherapy, by James P. McCullough Jr, PhD

Effects of Psychotherapy on Brain Function, by Gabriel S. Dichter, PhD, Jennifer N. Felder, and Moria Smoski, PhD



1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-3105.
2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluations of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
3. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200.
4. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.
5. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262:914-919.
6. Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63:963-971.
7. Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry. 2003;53:640-648.
8. Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depressive disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982;39:905-910.
9. Sackheim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62 (suppl 16):10-17.
10. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.
11. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(suppl 8):17-25.
12. Bauer M, Bschor T, Pfennig A, et al; WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
13. Nierenberg AA, McLean NE, Alpert JE, et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry. 1995:152:1500-1503.
14. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342-351.
15. Beesdo K, Bittner A, Pine DS, et al. Incidence of social anxiety disorder and consistent risk for secondary depression in the first three decades of life. Arch Gen Psychiatry. 2007;64:903-912.
16. Greco T, Eckert G, Kroenke K. The outcome of physical symptoms with treatment of depression. J Gen Intern Med. 2004;19:813-818.
17. Bair MJ, Robinson RL, Eckert GJ, et al. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004;66:17-22.
18. Fava M, Mallinckrodt CH, Detke MJ, et al. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry. 2004;65:521-530.
19. Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry. 2004;65 (suppl 16):27-32.
20. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59:1052-1060.
21. Davis LL, Frazier E, Husain MM, et al. Substance use disorder in major depressive disorder: a confirmatory analysis of the STAR*D cohort. Am J Addict. 2006;15:278-285.
22. Davis LL, Rush JA, Wisniewski SR, et al. Substance use disorder comorbidity in major depressive disorder: an exploratory analysis of the Sequenced Treatment Alternatives to Relieve Depression cohort. Compr Psychiatry. 2005;46:81-89.
23. Sher L, Stanley BH, Harkavy-Friedman JM, et al. Depressed patients with co-occurring alcohol use disorders: a unique patient population. J Clin Psychiatry. 2008;69:907-915.
24. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.
25. Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder still underdiagnosed? Are antidepressants overutilized? J Affect Disord. 1999;52:135-144.
26. Akiskal HS. The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions. J Affect Disord. 2005;84:107-115.
27. Amsterdam JD, Shults J. Comparison of short-term venlafaxine versus lithium monotherapy for bipolar II major depressive episode: a randomized open-label study. J Clin Psychopharmacology. 2008; 28:171-181.
28. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Clin Psychiatry. 2007;68: 1472-1479.
29. Pliszka SR. Comorbidity of attention-deficit/hyperactivity disorder with psychiatric disorder: an overview. J Clin Psychiatry. 1998;59(suppl 7):50-58. 
30. Wilens TE, Kwon A, Tanguay S, et al. Characteristics of adults with attention deficit hyperactivity disorder plus substance use disorder: the role of psychiatric comorbidity. Am J Addict. 2005;14:319-327. 
31. Fischer AG, Bau CHD, Grevet EH, et al. The role of comorbid major depressive disorder in the clinical presentation of adult ADHD. J Psychiatr Res. 2007;41: 991-996.
32. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
33. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder. A second multicenter, randomized double-blind placebo-controlled study. J Clin Psychopharmacol. 2008;28:156-165. 
34. Leuchter AF, Cook IA, Marangell LB, et al. Biomarkers for rapid identification of treatment effectiveness in major depression: predictors of response and remission to antidepressant treatment. Poster presented at: Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting; May 27-30, 2008; Phoenix. 
35. Rasmussen-Torvik LJ, McAlpine DD. Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils. Depress Anxiety. 2007;24:350-357.
36. McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with the outcome of antidepressant treatment. Am J Hum Genet. 2006;78:804-814.
37. Paddock S, Laje G, Charney D, et al. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007;164:1181-1188.
38. Uhr M, Tontsch A, Namendorf C, et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron. 2008;57:203-209.
39. Hu XZ, Rush AJ, Charney D, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64:783-792.
40. Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007;164:1530-1538.



This article focuses on recent innovations in diagnostic issues, tactics, and strategy, and takes a brief look at the future.

Author | James G. Barbee, MD

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