Initial Antidepressant Therapy Research Articles

Predictors of Quality of Life Improvement with Escitalopram and Adjunctive Aripiprazole in Patients with Major Depressive Disorder: A CAN-BIND Study Report.

Non-response to first-line treatment for major depressive disorder (MDD) is common; for such individuals, quality of life (QoL) impairments can be severe. Identifying predictors of QoL changes may support the management of cases with persistent depressive symptoms despite adequate initial pharmacological/psychological treatment. The present study aimed to explore predictors of domain-specific QoL improvement following adjunctive aripiprazole treatment for inadequate response to initial antidepressant therapy. We evaluated secondary QoL outcomes from a CAN-BIND (Canadian Biomarker Integration Network in Depression) study in patients with MDD who did not respond to an initial 8 weeks of escitalopram and received a further 8 weeks of adjunctive aripiprazole (n = 96). Physical, psychological, social, and environmental QoL domains were assessed using the World Health Organization QoL Scale Brief Version (WHOQOL-BREF). Clinician-rated depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Functioning was measured with the Sheehan Disability Scale (SDS). Satisfaction with medication was assessed with a single item from the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Exploratory t-tests were used to describe domain score changes. A hierarchical linear regression was used to explore demographic, clinical, and treatment-related predictors of improvement. Across domains, QoL improved with adjunctive aripiprazole treatment. Satisfaction with medication and MADRS and SDS scores similarly improved. Symptom reduction was a predictor for positive change to physical and psychological QoL; functioning improvements were predictive of increases to all QoL domains. Satisfaction with medication predicted improvements to physical and psychological domains, whereas number of medication trials was a predictor of worsening QoL in the physical domain. The final model explained the most variance in psychological (68%) and physical (67%) QoL. Less variance was explained for environmental (43%) and social QoL (33%), highlighting a need for further exploration of predictors in these domains. Strategies such as functional remediation may have potential to support QoL for individuals with persistent depressive symptoms. ClinicalTrials.gov identifier: NCT016557.

Predicting Neuroimaging Biomarkers for Antidepressant Selection in Early Treatment of Depression.

Due to the biological heterogeneity, 60%-70% of patients with major depressive disorder (MDD) do not respond to or achieve remission from first-line antidepressants. Predicting neuroimaging biomarkers for early antidepressant treatment could guide initial antidepressant therapy. To assess for neuroimaging biomarkers for antidepressant selection in early antidepressant treatment. Prospective. A total of 85 MDD patients from the major site and 33 MDD patients from an out-of-sample test site. A 3.0 T, T1-weighted imaging using a magnetization-prepared rapid acquisition gradient-echo sequence and diffusion tensor imaging (DTI) using an echo-planar sequence. Baseline DTI data of patients who achieved early improvement after 2-weeks of antidepressant treatment (selective serotonin reuptake inhibitors [SSRI] or serotonin-norepinephrine reuptake inhibitors [SNRI]) were analyzed. An ensemble model was constructed using data from the major site and then applied to assess the early response of patients at the out-of-sample test site. Support vector machine combined with leave-one-out cross-validation were applied to construct the whole model from individual base models from different brain regions. Discriminative biomarkers were evaluated by calculating the changes in sensitivity and specificity obtained when removing a single base model from the whole model, the base model being removed changing in each run. Training performance over MDD patients at the major site achieved 75% accuracy while performance with accuracy of 70% was achieved in the out-of-sample test site. Assessing sensitivity and specificity changes following the removal of single base models from the prominent model highlighted the functions of two neural circuitries: SSRI-related emotion regulation circuitry, centered on the hippocampus (sensitivity changes: 10%) and amygdala (sensitivity changes: 11%); and SNRI-related emotion and reward circuitry, centered on the putamen (specificity changes: 8%) and orbital part of superior frontal gyrus (specificity changes: 12%). These findings support future research on clinical antidepressant selection for MDD. 1 TECHNICAL EFFICACY: Stage 2.

Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

Changes in antidepressant therapy should be considered early in patients with inadequate response to a first-line agent.

Deciding when and how to change treatment in patients with major depressive disorder who have inadequate response to initial antidepressant therapy is an important everyday clinical question. Here, we ask whether an early change of approach is superior to a delayed change. We consider the recommendations provided by recent guidelines, examine the evidence behind this guidance and suggest a decision tree to clarify treatment options and timing. Both the early and late-change strategies may have their place in clinical practice. However, we take the view that an earlier than currently usual change in antidepressant treatment should be considered more frequently in cases of non-response. Specific studies are needed to identify and to better understand predictors of early and late response.

Intramuscular Testosterone Supplementation Ameliorates Depression in Hypogonadal Men: A Retrospective Study in an Outpatient Department.

Substantial evidence has indicated an association between hypogonadism and depressive symptoms, which led to the conduction of studies that found an ameliorating effect of testosterone (T) supplementation (S) upon depression in men. Retrospective analysis of medical records identified 16 depressed, hypogonadal men who have not responded adequately to initial antidepressant therapy and subsequently received intramuscular T injections. Following the proposal of Button et al., a minimal clinically important difference was defined as an 18% reduction of the Beck Depression Inventory-II (BDI-II) score. After TS, the BDI-II score decreased by approximately 31% (p<0.01), from 27.2 (mean; standard deviation [SD] 11.8) to 18.8 (mean; SD 11.3). Patients with baseline BDI-II scores ranging from 29 to 63 (severe depression) showed a significantly higher absolute and relative reduction through TS. Also, men with a shorter depression duration (<2 years) demonstrated a greater benefit. The depressed, hypogonadal men generally benefited from TS given that the BDI-II score reduction was almost twice as much as needed for a minimal clinically important difference.

Associations Between Medication Class and Subsequent Augmentation of Depression Treatment in Privately Insured US Adults.

Treatment augmentation is an important clinical decision in the pharmacotherapy for depression, yet few studies have examined the rates of treatment augmentation by medication class. The aim of this study was to examine which initial pharmacotherapies for depression are more likely than others to result in subsequent treatment augmentation. This study is a retrospective cohort analysis of administrative data of 214,705 privately insured US adults between the age of 18 and 64 years who were diagnosed with a new episode of depression in 2009. Propensity score-adjusted logistic regression and Cox regression were used to model the effect of the class of initial monotherapy on treatment augmentation. Risk adjustors included depression severity, comorbidities, provider type, insurance, and demographic characteristics. The class of initial monotherapy and the health care provider type were the main independent variables of interest. The outcome was the augmentation of monotherapy. Thirty-four percent of individuals received treatment augmentation. Compared with selective serotonin reuptake inhibitor monotherapy, second-generation antipsychotics as the initial treatment were associated with significant increase in the likelihood of augmentation compared with the other classes (hazards ratio, 2.59; 95% confidence interval [CI], 2.51-2.68). This result was corroborated after propensity score adjustment (odds ratio, 2.85; 95% CI, 2.70-3.00) when comparing second-generation antipsychotics to the other classes of pharmacotherapy. The other significant predictor of treatment augmentation was the provider type. Mental health specialists were 27% more likely to augment a treatment compared with generalists (hazards ratio, 1.27; 95% CI, 1.25-1.30). The type of initial antidepressant therapy is associated with the chances of treatment augmentation. Second-generation antipsychotics progressed to augmentation more rapidly than the other classes.

Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial

BackgroundThe treatment of depression remains a challenge since at least 40% of patients do not respond to initial antidepressant therapy and 20% present chronic symptoms (more than 2 years despite standard treatment administered correctly). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy but still not ideal. Intermittent Theta Burst Stimulation (iTBS), which has only been used recently in clinical practice, could have a faster and more intense effect compared to conventional protocols, including 10-Hz high-frequency rTMS (HF-rTMS). However, no controlled study has so far highlighted the superiority of iTBS in resistant unipolar depression.Methods/designThis paper focuses on the design of a randomised, controlled, double-blind, single-centre study with two parallel arms, carried out in France, in an attempt to assess the efficacy of an iTBS protocol versus a standard HF- rTMS protocol. Sixty patients aged between 18 and 75 years of age will be enrolled. They must be diagnosed with major depressive disorder persisting despite treatment with two antidepressants at an effective dose over a period of 6 weeks during the current episode. The study will consist of two phases: a treatment phase comprising 20 sessions of rTMS to the left dorsolateral prefrontal cortex, localised via a neuronavigation system and a 6-month longitudinal follow-up. The primary endpoint will be the number of responders per group, defined by a decrease of at least 50% in the initial score on the Montgomery and Asberg Rating Scale (MADRS) at the end of rTMS sessions. The secondary endpoints will be: response rate 1 month after rTMS sessions; number of remissions defined by a MADRS score of <8 at the endpoint and 1 month after; the number of responses and remissions maintained over the next 6 months; quality of life; and the presence of predictive markers of the therapeutic response: clinical (dimensional scales), neuropsychological (evaluation of cognitive functions), motor (objective motor testing) and neurophysiological (cortical excitability measurements).DiscussionThe purpose of our study is to check the assumption of iTBS superiority in the management of unipolar depression and we will discuss its effect over time. In case of a significant increase in the number of therapeutic responses with a prolonged effect, the iTBS protocol could be considered a first-line protocol in resistant unipolar depression.Trial registrationClinicalTrials.gov, Identifier NCT02376491. Registered on 17 February 2015 at http://clinicaltrials.gov.

Treatment augmentation effects of EMDR intervention after traumatic experiences in patients with major depression: a case series

Depression is a frequent disorder that may have a recurring and chronic course with a potentially serious impact on morbidity and mortality. While around half of the patients show an inadequate response to initial antidepressant therapy, as many as 20% of patients with chronic depression do not benefit from any other alternative drugs. In this case series, three patients diagnosed with depression were treated with Eye Movement Desensitization and Reprocessing (EMDR). Three women (aged 28-44 years) diagnosed with depression were admitted to EMDR therapy. All patients actually underwent antidepressant treatment. Two patients received 150mg/day venlafaxine and mirtazapine, one patient 300mg/day bupropion and 30mg/day mirtazapine. Six to eight sessions of EMDR were applied to the patients. Before and after treatment, patients completed Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and State-Trait Anxiety Inventory (STAI). After treatment, there was a statistically significant reduction in patient-reported BDI, BAI, and STAI scores. EMDR therapy augmentation was effective in the treatment of patients with depression.

Effect of symptom severity on efficacy and safety of aripiprazole adjunctive to antidepressant monotherapy in major depressive disorder: A pooled analysis

BackgroundThere is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. MethodsData from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25–30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. ResultsAripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, −2.5 [−4.0 to −1.1]; moderate, −3.2 [−4.9 to −1.6]; severe, −4.5 [−6.8 to −2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. LimitationsThe original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. ConclusionsIn patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. Clinical trial registrationClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758.

Prevention of Relapse and Recurrence of Bipolar Type I Depression: A Study Protocol for a Multi-site Randomized, Double-blind, Placebo-substitution Trial

Background: Bipolar (BP) I disorder affects 1.6% of the US adult population and results in estimated healthcare costs of $40 billion annually. It is characterized by a predominance of major depressive episodes interspersed with manic and hypomanic episodes. Most current practice guidelines are based upon expert consensus and generally recommend using mood stabilizer monotherapy for initial treatment of BP I depression, while avoiding antidepressants and using only mood stabilizer monotherapy for prevention of relapse and recurrence of depression. We hypothesize that long-term mood stabilizer plus antidepressant therapy will result in fewer depressive relapses and recurrences versus mood stabilizer monotherapy. Methods/design: 200 patients with BP I depression will receive initial lithium plus fluoxetine therapy for 12 weeks. Responders will be randomized to double-blind maintenance therapy with either: (i) lithium plus fluoxetine, or (ii) lithium monotherapy (following fluoxetine taper and discontinuation) for an additional 50 weeks. The primary outcome is the proportion of subjects in each condition who have a depressive relapse or recurrence during maintenance therapy. Depressive relapse or recurrence is defined as a return of moderate depressive symptoms. Discussion: We believe that evidence-based medicine will eventually support the use of concurrent antidepressant therapy for prevention of depressive relapse and recurrence in patients with BP I disorder. The paucity of modern controlled clinical trials studying the best method for preventing depressive relapse and recurrence of BP I disorder has led to contradictory practice guidelines and confusion as to the best treatment for BP I disorder. This study seeks to determine whether subjects who respond to initial mood stabilizer plus antidepressant therapy will have a superior longterm efficacy and fewer depressive relapses and recurrences if they continue therapy with maintenance mood stabilizer plus antidepressant therapy versus mood stabilizer therapy alone. Trial registration: ClinicalTrials.gov Trials Register - NCT00961961.

Beneficial Effects of Adjunctive Aripiprazole in Major Depressive Disorder Are Not Dependent on Antidepressant Therapy History

To determine whether switching within or between antidepressant therapy (ADT) classes prior to the use of adjunctive antipsychotic treatment is associated with different outcomes in major depressive disorder (MDD). This was a post hoc analysis of pooled data from 3 similar, multicenter, randomized, double-blind, placebo-controlled registrational studies of aripiprazole adjunctive to ADT conducted between September 2004 and April 2008. The trials comprised the following 3 phases: a 7- to 28-day screening phase, an 8-week single-blind prospective treatment phase, and a 6-week double-blind, randomized phase. Patients were aged 18-65 years and met DSM-IV-TR criteria for MDD. Patients with an inadequate response to ADT during the screening phase entered the prospective treatment phase, during which they were switched to another ADT medication of either the same or a different class. Those patients with an inadequate response were then randomized to double-blind adjunctive aripiprazole or adjunctive placebo and followed for 6 weeks. Mean improvement in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole versus adjunctive placebo for both between-class (-9.2 vs -6.2, P < .001) and within-class (-9.8 vs -6.6, P < .001) switch groups. Relative risks for response were 1.6 (95% CI = 1.3-2.1) for those who switched between classes and 1.7 (95% CI = 1.2-2.2) for those who switched within class. Augmentation with aripiprazole, after either a between-class or within-class switch following initial ADT failure, is an effective option for patients with nonresponsive MDD. In contrast to current strategies employed in clinical practice, these results suggest that adjunctive aripiprazole is a logical strategy in patients unresponsive to ADT. ClinicalTrials.gov identifiers: NCT00105196, NCT00095758, NCT00095823.

Efficacy of adjunctive aripiprazole in patients with major depressive disorder who showed minimal response to initial antidepressant therapy

To evaluate the efficacy of adjunctive aripiprazole in patients with minimal response to prior antidepressant therapy (ADT). Pooled data from three randomized, double-blind, placebo-controlled studies assessing the efficacy of adjunctive aripiprazole to ADT in patients with major depressive disorder who had a minimal response [< 25% reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS)] to an 8-week prospective ADT. During the 6-week, double-blind adjunctive phase, response was defined as at least 50% reduction in the MADRS score and remission as at least 50% reduction in MADRS score and a MADRS score ≤ 10. Rates were examined using analysis of covariance and Cochran-Mantel-Haenszel tests. Kaplan-Meier curves were used to calculate time to response and remission. Of 1038 patients, 72% (n=746) exhibited a minimal response to ADT (ADT minimal responder). Time to response and remission were significantly shorter for ADT minimal responders receiving aripiprazole+ADT versus adjunctive placebo+ADT. ADT minimal responders on aripiprazole+ADT showed significantly greater improvements in MADRS score at endpoint compared with minimal responders on placebo+ADT (-10.3 vs. -6.5, P<0.0001). In addition, ADT minimal responders exhibited significantly higher response rates with aripiprazole+ADT than placebo+ADT (36 vs. 19%, respectively, P<0.0001) and higher remission rates (24 vs. 12%, respectively, P<0.0001). The numbers needed to treat with aripiprazole+ADT were six for response and eight for remission. Aripiprazole augmentation had a rapid and clinically meaningful effect in ADT minimal responders.

C.14.01 DEBATE: Managing inadequate response to initial antidepressant therapy: to switch or not to switch?

Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-d-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX-13, NRX-1047, Ro25-6981, LY392098, LY341495, d-cycloserine, d-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression.

Atypical Antipsychotics and Other Therapeutic Options for Treatment of Resistant Major Depressive Disorder

Antidepressant therapies, such as selective serotonin reuptake inhibitors (SSRIs), are current first-line treatments for Major Depressive Disorder. However, over 50% of treated patients show an inadequate response to initial antidepressant therapy. If the therapeutic outcomes from two antidepressant therapies are suboptimal, potentially resulting in Treatment Resistant Depression, subsequent strategies include switching to another antidepressant or augmenting treatment by combining with other agents. When combined with SSRIs, atypical antipsychotics have supplementary action on dopaminergic and noradrenergic systems. Studies on combined treatment with atypical antipsychotics have shown significantly increased remission rates, shortened response times, and favorable side effects. Augmentation of antidepressants with atypical antipsychotics is now an acceptable treatment strategy which leads to increased remission rates and better outcomes for patients.

How Do You Choose a Second-Line Treatment Option for Depression?

A majority of patients with major depression do not remit or adequately respond to initial antidepressant therapy. When response is insufficient, a diagnosis of depression and any comorbidities should be confirmed, treatment adherence should be established, and antidepressant dosages should be optimized as tolerated. If response is still insufficient, then implementing second-line treatment strategies is warranted. Second-line strategies of switching to or combining/augmenting the initial agent with one of a variety of antidepressant medications and/or psychotherapies improves remission rates, although no single approach or agent has demonstrated clear superiority over any other. Second-line treatment selections should be driven by safety considerations, patients' symptom profiles, and patient preference. Comorbid medical conditions, especially cardiac and cerebrovascular complications, and potential drug-drug interactions should be considered when making treatment decisions.

Systematic Review of Lithium Augmentation in Depression Resistant to at Least 2 Antidepressants

To the Editor: Refractory depression is common in clinical practice. At least 30% of patients fail to respond to initial antidepressant therapy.1 In patients who have failed 1 course of antidepressants, there is evidence from 9 randomized controlled trials suggesting that approximately 50% of treatment-refractory patients do respond to lithium augmentation compared with placebo (p < .001).2 The British Association for Psychopharmacology guidelines recommend that patients be treated with 2 antidepressants before an augmentation strategy is used.3 Our aim was to review the evidence for use of lithium in those patients who are resistant to treatment with 2 or more antidepressants at recognized therapeutic doses. Method. A systematic review was undertaken of placebo-controlled, double-blind, randomized trials of lithium that assess its effectiveness in treatment-resistant depression. English-language studies of adults (aged 18 years or older; both sexes), suffering from major depressive disorder diagnosed by the International Classification of Diseases, Tenth Revision (ICD-10), the Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or Research Diagnostic Criteria (RDC) were included. The following keywords were used: lithium OR Camcolit OR Carbolith OR Duralith OR Eskalith OR Licarbium OR Liskonum OR Litarex OR Lithane OR Lithocarb OR Lithizine OR Lithonate OR Lithotabs OR Manialith OR Phasal OR Priadel OR Quilonorm OR Quilonum OR Li-Liquid OR resistant depression OR refractory depression OR treatment resistant depression OR treatment non respon(*) depression OR lithium augment(*). Exclusion criteria were bipolar depression, previous prescription of lithium, co-morbid schizophrenia, or drug and alcohol dependence. All participants should have received 2 antidepressants at recognized therapeutic doses (eg, 150 mg of imipramine daily) for a minimum of 4 weeks. Participants in the active arm should have received at least 4 weeks of lithium treatment at a minimum plasma level of 0.4 mmol/L or a dose of 600 mg daily. The search included the computerized databases of the Cochrane Library, MEDLINE/PubMed (1966+), EMBASE (1980+), CINAHL (1982+), and PsycINFO (1974+). Reference lists were hand searched along with major books. Pharmaceutical companies were contacted. Leading researchers and experts in the field were also contacted. Methodological quality was categorized as (A) adequate, (B) uncertain, or (C) inadequate. Results. A total of 12 randomized controlled trials involving lithium augmentation for resistant depression were identified, of which only 14 had ensured a trial of 2 antidepressants. There was little information given in the published reports regarding the methods used to achieve random allocation. Thus, on the basis of the published reports, the studies initially received a B rating according to the Cochrane criteria. In the 1 study that included 2 antidepressants,4 there were 18 patients in the lithium augmentation arm, of whom 2 dropped out. The proportion who responded to lithium augmentation in the completer and intent-to-treat (ITT) analyses were 12.5% and 11.1%, respectively. There was no statistically significant difference in scores on the 17-item Hamilton Rating Scale for Depression. The lithium group achieved a mean reduction of 6.3/5.5 points (completer/ITT). The mean reduction in the placebo group was 6.5/5.8 points (completer/ITT) (p = .91). The mean blood lithium level at week 2 was 0.63 mmol/L (range, 0.3–1.4 mmol/L) and at week 6 was 0.61 mmol/L (range, 0.6–0.9 mmol/L). The duration of the trial was 6 weeks. In the recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,5 there was no placebo group, and, as there was no significant difference to T3 augmentation (which has not yet been demonstrated as being effective for treatment-resistant depression), we cannot conclude that either lithium or T3 is an effective augmentation strategy for patients who are resistant to at least 2 antidepressants. There is limited evidence to support the use of lithium augmentation after 2 or more failed antidepressant therapies. More research needs to be undertaken to compare lithium augmentation with other augmentation strategies. Those patients who have failed to respond to 2 or more antidepressants are a difficult group to treat.

Treatment Options for the Patient Who Does Not Respond Well to Initial Antidepressant Therapy

This column is the third in a series that began in January, 2009 on the improved understanding of and ability to treat patients with major depression. This column focuses on options for the patient who has not benefitted from one or more adequate trials of currently available antidepressants. It begins with a summary of the results of the switching and augmentation strategies studied in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, funded by the National Institute of Mental Health (NIMH). The column then discusses options not included in the STAR*D study, including aripiprazole, which is now the first medication approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for the treatment of patients with clinical depression, and vagus nerve stimulation, delivered by the first implantable device approved by the FDA for the treatment of patients with treatment-resistant depression (TRD). The goal of this column to summarize the data supporting various options for the busy clinician who treats such patients.

Getting Better, Getting Well

In general, the pharmacological treatment of non-psychotic major depressive disorder in old age is only partially successful, with only approximately 50% of older depressed adults improving with initial antidepressant monotherapy. Many factors may predict a more difficult-to-treat depression, including coexisting anxiety, low self-esteem, poor sleep and a high coexisting medical burden. Being aware of these and other predictors of a difficult-to-treat depression gives the clinician more reasonable expectations about a patient's likely treatment course. If an initial antidepressant trial fails, the clinician has two pharmacological options: switch or augment/combine antidepressant therapies. About 50% of patients who do not improve after initial antidepressant therapy will respond to either strategy. Switching has several advantages including fewer adverse effects, improved treatment adherence and reduced expense. However, as a general guideline, if patients are partial responders at 6 weeks, they will likely be full responders by 12 weeks. Thus, changing medication is not indicated in this context. However, if patients are partial responders at 12 weeks, switching to a new agent is advised. If the clinician treats vigorously and if the patient and clinician persevere, up to 90% of older depressed patients will respond to pharmacological treatment. Furthermore, electroconvulsive therapy is a safe and effective non-pharmacological strategy for non-psychotic major depression that fails to respond to pharmacotherapy. Getting well and staying well is the goal; thus, clinicians should treat to remission, not merely to response. Subsequently, maintenance treatment with the same regimen that has been successful in relieving the depression strongly improves the patient's chances of remaining depression free.

Improving the chance of recovery from the short- and long-term consequences of depression

Major depressive disorder (MDD) is a common, chronic disorder that requires long-term management. Although effective treatments are available, MDD frequently remains undiagnosed. Furthermore, once recognized, treatment duration and dosage are often inadequate and adherence to medication is often poor. However, adequate acute phase treatment of MDD is essential to reduce symptomatology, and improve quality of life and the clinical course. After remission, treatment should be continued for 4-9 months to consolidate the remission and prevent relapse. For patients who do not respond adequately to their initial antidepressant therapy, switching or augmentation of therapy may be necessary. Many patients suffer residual symptomatology, even when classified as being in remission. In addition to the suffering and impairment that this causes, residual symptomatology is associated with a high rate of relapse. Clinicians should strive to achieve asymptomatic recovery both in terms of core symptomatology and psychosocial disability. This requires appropriate treatment at therapeutic doses for a sufficient duration; education and support to promote patient compliance with treatment; and regular monitoring and prompt intervention for patients with symptoms that persist even at subsyndromal levels. In conclusion, there remains considerable scope for improving the identification, treatment and management of patients with MDD.

Improving the chance of recovery from the short- and long-term consequences of depression.

Major depressive disorder (MDD) is a common, chronic disorder that requires long-term management. Although effective treatments are available, MDD frequently remains undiagnosed. Furthermore, once recognized, treatment duration and dosage are often inadequate and adherence to medication is often poor. However, adequate acute phase treatment of MDD is essential to reduce symptomatology, and improve quality of life and the clinical course. After remission, treatment should be continued for 4-9 months to consolidate the remission and prevent relapse. For patients who do not respond adequately to their initial antidepressant therapy, switching or augmentation of therapy may be necessary. Many patients suffer residual symptomatology, even when classified as being in remission. In addition to the suffering and impairment that this causes, residual symptomatology is associated with a high rate of relapse. Clinicians should strive to achieve asymptomatic recovery both in terms of core symptomatology and psychosocial disability. This requires appropriate treatment at therapeutic doses for a sufficient duration; education and support to promote patient compliance with treatment; and regular monitoring and prompt intervention for patients with symptoms that persist even at subsyndromal levels. In conclusion, there remains considerable scope for improving the identification, treatment and management of patients with MDD.