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Richard C Shelton

Publications and source records attributed to Richard C Shelton.

At least 19 recordsLinked to original sources
PubMed2007

A randomized, double-blind, crossover trial of modafinil on mood.

Modafinil, a medication for the excessive sleepiness associated with narcolepsy, has been hypothesized to improve not just alertness but mood as well. The purpose of this study was to determine how treatment with modafinil affects mood in healthy volunteers. Normal healthy volunteers (n = 12, 10 men and 2 women; 30-44 years) underwent a 3-day, counterbalanced, randomized, crossover, inpatient trial of modafinil (400 mg daily) versus placebo with 4-day washout period between 2 treatments. Mood was assessed daily using both the Positive and Negative Affect Schedule and a general mood scale, which consisted of 10 bipolar adjective ratings based on a severity scale ranging from 1 to 10. Modafinil increased general mood and Negative Affect scales relative to placebo and had a significant effect on Positive Affect scales. These results suggest that modafinil may have general mood-elevating effects accompanied by increased negative affect (anxiety). The findings may have implications for clinical practice, in particular for the adjunctive use of modafinil in treatment-resistant depression.

Administration, Oral↗
PubMed2007

Randomized, double-blind, placebo-controlled crossover trials of venlafaxine for hot flashes after breast cancer.

BACKGROUND: Although venlafaxine reduces self-reported hot flashes, no data have established the drug's impact on physiologically documented hot flashes. Two randomized, double-blind, placebo-controlled crossover trials examined the efficacy of two doses of venlafaxine in relation to physiological and self-reported hot flashes and other outcomes, including negative affect, fatigue, sleep, and quality of life. METHODS SAMPLE: 57 breast cancer survivors in the low-dose study; 20 in the high-dose study. SETTING: university cancer clinics in the Southeast and Midwest. INTERVENTION: 37.5 mg of venlafaxine (low-dose study) or 75 mg of venlafaxine (high-dose study). MEASURES: hot flash frequency (physiological monitor, diary, and event marker), hot flash severity (diary), hot flash bother (diary), and questionnaires for hot flash impact on daily life, negative affect, fatigue, sleep, and quality of life. RESULTS: Subjective but not physiological hot flash measures showed placebo effects. Venlafaxine resulted in modest decreases in hot flashes, but only hot flash interference improved differentially at the higher dose. The timing of venlafaxine's effects on hot flashes varied by dose. Only women with a > or =50% decrease in physiological hot flashes experienced significant improvement in fatigue, sleep quality, and quality of life. Although side effects were mild, most patients discontinued venlafaxine long-term. CONCLUSIONS: Although venlafaxine resulted in modest and acute reductions in hot flashes with few side effects, it may not be tolerable to some patients long-term. At least 50% relief in physiological hot flashes may be needed for patients to demonstrate improvement in other outcomes, including decreased fatigue, improved sleep, and improved quality of life.

Adult↗
PubMed2006

Polymorphisms in the regulatory region of the human serotonin 5-HT2A receptor gene (HTR2A) influence gene expression.

BACKGROUND: Genomic variation in the regulatory region of the serotonin (5-HT) 2A receptor gene (HTR2A) may contribute to altered levels of 5-HT2A receptor and to psychiatric disease. METHODS: Frequency and linkage disequilibrium (LD) were determined for promoter single nucleotide polymorphisms (SNPs) -1438A/G, -1420C/T, and -783A/G in 156 subjects. Functional relevance of -1438A/G and -783A/G was assayed in vitro using a luciferase reporter assay and ex vivo using quantitative real time polymerase chain reaction in a set of human fibroblast cell lines. RESULTS: Significant LD was observed between SNPs -1438A/G and -783A/G. In vitro assays showed no significant differences in promoter activity between the A- and G-allele of -1438 locus when expressed with the major alleles at -1420C/T and -783A/G; however, when the minor allele G at -783 was expressed with G-allele at -1438, promoter activity was significantly decreased. 5-HT2A receptor mRNA expression in human fibroblast cell lines confirmed that -783A/G polymorphism significantly modified the effects of -1438A/G SNP. CONCLUSIONS: Our results demonstrate that SNP -783A/G modifies the effects of the major SNP -1438A/G. Future studies examining the association of -1438A/G polymorphism with diseases and 5-HT2A receptor expression analyses should account for this epistasis.

Adult↗
PubMed2006

Treatment with venlafaxine extended release after SSRI nonresponse or intolerance: a randomized comparison of standard- and higher-dosing strategies.

OBJECTIVE: Evaluate efficacy of standard and higher doses of venlafaxine extended release (ER) in depressed outpatients who had either not responded to or could not tolerate an adequate trial of therapy with a selective serotonin reuptake inhibitor (SSRI). METHODS: Outpatients (n = 232) with major depressive disorder were randomly assigned to 8 weeks of treatment with either "standard" (n = 119; mean dose = 148 mg/d) or "higher" (n = 113; mean dose = 309 mg/d) dosage therapies. Between weeks 8 and 12, nonresponders in the standard dose group could receive higher dose therapy. RESULTS: Response rates in the higher dose group were significantly greater at week 8 on the Clinical Global Impressions-Improvement scale (68% vs 52%; P < 0.001) and Patient Global Impressions scale (intent-to- treat; 68% vs 52%; P < 0.001). The dosing strategies did not, however, differ significantly in change in HAM-D21 total score or HAM-D21 response or remission rates. At week 12, there were no significant efficacy differences between the two groups in the intent-to-treat sample. Five side effects (constipation, sweating, hypertension, agitation, and urinary frequency) were more common in the high-dose group. CONCLUSIONS: Higher dose therapy with venlafaxine ER (ie, 300-375 mg/d) resulted in a more rapid response on some measures, but was not as well tolerated as therapy at standard doses. Although these data provide further evidence of a dose-response relationship for venlafaxine therapy results suggest that slower titration to higher doses of venlafaxine ER may improve tolerability without greatly diminishing the probability of success.

Adult↗
PubMed2006

Detection of an mRNA polymorphism by differential display.

Differential display technology was utilized to compare programs of gene expression in primary cultures of human skin fibroblasts from normal volunteers and patients diagnosed with melancholic depression. Polymorphic transcripts of a single gene differing by one tandem repeat sequence of four nucleotides (TGAT) in the 3' noncoding region were detected.

Base Sequence↗
PubMed2006

Olanzapine/fluoxetine combination for bipolar depression.

Bipolar depression remains one of the most difficult to treat of all mental disorders. Until recently, no treatments, including antidepressants, have consistently shown to be effective in this condition. Olanzapine, an atypical antipsychotic, has been approved by the US Food and Drug Administration for the acute treatment of mania and maintenance prevention of relapse into depression or mania. A clinical trial tested the relative effectiveness of the combination of olanzapine and fluoxetine in bipolar type I depression, against olanzapine alone or placebo. The combination produced a very robust clinical effect acutely and a long-term follow-up study indicated that there was a low rate of induction of mania or mixed states. Therefore, the olanzapine/fluoxetine combination represents a viable alternative for bipolar depression. However, uptake of this combined product in practice has been modest. This is likely to be the result of several factors, including resistance to the use of fixed combination preparations and, more recently, evidence of effectiveness of the atypical quetiapine and the anticonvulsant lamotrigine. Perhaps the greatest resistance to the use of olanzapine alone or in combination has been the problem of weight gain and the attendant risk of type 2 diabetes and the metabolic syndrome. Vigorous management of this problem has been shown to mitigate the potential for weight gain and is required if this combination is to be used. However, many clinicians find management of weight gain in olanzapine treated patients a challenge. In addition, weight, waist circumference, lipids and glucose should be monitored.

Antidepressive Agents↗
PubMed2006

A randomized, double-blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder.

OBJECTIVE: Sertraline may produce dual neurotransmitter effects similar to the serotonin-norepinephrine reuptake inhibitors (SNRIs); however, it has been tested against an SNRI in only 1 previous study, and never at an optimal dose. The objective of the current multisite study was to compare relatively higher doses of sertraline (i.e., 150 mg/day) and venlafaxine extended release (XR) (225 mg/day) in outpatients with major depressive disorder. METHOD: Subjects with DSM-IV major depressive disorder were randomly assigned to 8 weeks of double-blind treatment with sertraline (N = 82) or venlafaxine XR (N = 78). The study ran from January 2002 through January 2003. The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Questionnaire; secondary outcome variables included the 17-item Hamilton Rating Scale for Depression. RESULTS: Both treatments led to significant improvement in depressive symptoms and quality-of-life measures. No significant differences were noted between treatment groups for final scores on the primary or secondary measures. The treatment groups did not differ significantly in the percentage of responders (sertraline = 55%, venlafaxine XR = 65%; intent-to-treat [ITT] sample) or remitters (sertra-line = 38%, venlafaxine XR = 49%; ITT sample), although the proportions are similar to those found in earlier selective serotonin reuptake inhibitor (SSRI) vs. venlafaxine meta-analyses. In patients who achieved the maximum dose of drug and maintained it for 3 weeks, response rates were similar to those found at lower doses (sertraline = 59%, venlafaxine XR = 70%); however, remission rates for this sample were comparable for both drug groups (sertraline = 48%, venlafaxine XR = 50%). CONCLUSIONS: The efficacies of sertraline and venlafaxine XR were comparable. Although response and remission rates did not differ statistically, the rates were analogous to those reported in previous meta-analyses. However, at clinically relevant higher doses, the remission rates were very similar. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00179283.

Adult↗
PubMed2006

The nature of the discontinuation syndrome associated with antidepressant drugs.

A common phenomenon accompanying treatment with nearly every major class of antidepressant is the emergence of the discontinuation syndrome in some patients. It is seen most frequently after the abrupt cessation of agents with shorter half-lives. The term withdrawal has been used in the past; however, the distinctions between discontinuation symptoms and drug withdrawal are clear. Thus, the use of proper terminology when discussing this phenomenon with patients will help to alleviate concerns and stop the spread of common misperceptions. In addition, awareness of the unique nature of discontinuation effects and a grasp of the typical time frame of their emergence can assist in distinguishing between discontinuation syndrome and relapse. As a result, it is vital that both patients and their relatives, especially caregivers, be provided with adequate education and a realistic and objective appraisal of expected outcomes upon initiation of antidepressant treatment.

Antidepressive Agents↗
PubMed2006

Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research.

OBJECTIVE: Currently, no evidence-based guidelines exist for the management of serotonin reuptake inhibitor (SRI) discontinuation syndrome. This article summarizes recommendations with respect to future research as well as clinical management recommendations for SRI discontinuation syndrome. PARTICIPANTS: In April 2004, a panel of physicians convened in New York City to discuss recommendations for clinical management of and additional research on SRI discontinuation syndrome. EVIDENCE: Previous guidance for management of SRI discontinuation syndrome was proposed in 1997 in a consensus meeting also chaired by Alan F. Schatzberg. A literature search of the PubMed database was conducted to identify articles on SRI discontinuation syndrome that have been published since 1997. CONSENSUS PROCESS: The 2004 panel reviewed important preclinical and clinical studies, discussed prospective investigation of this syndrome in clinical trials, and suggested the establishment of a research network to collect data in naturalistic settings. The panel also reviewed the management recommendations published in 1997 and subsequently updated the recommendations, taking into account the latest clinical data as well as the personal experience of its members with patients. CONCLUSIONS: Additional preclinical and clinical studies are necessary to further elucidate the underlying biological mechanisms of SRI discontinuation syndrome and to identify the patient populations and agents that are most affected by this phenomenon. Management strategies include gradual tapering of doses and should emphasize clinical monitoring and patient education.

Antidepressive Agents↗
PubMed2005

Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial.

OBJECTIVES: Recurrent depression predicts risk for subsequent episodes, but it is unclear how it relates to demographic features, course of illness, and clinical presentation. METHODS: We report on the baseline data for the first 1500 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org). Patients were required to have a DSM-IV diagnosis of nonpsychotic major depression and to score > or = 14 on the 17-item Hamilton rating scale for depression. Status with respect to recurrent depression and other aspects of illness course and demographic features were ascertained at intake, along with measures of depression and concurrent general medical illness. RESULTS: Patients with recurrent depression were older, had an earlier age of onset, and were more likely to have a positive family history of depression than first episode patients. However, recurrent patients were less likely to be chronic and reported shorter current episodes than first episode patients, something that was largely confined to females. Recurrent patients were more likely than first episode patients to report non-essential aspects of mood, cognition, and somatic symptoms, although largely as a consequence of greater overall depressive symptom severity. CONCLUSIONS: As compared to single episode depressions, recurrent depression was associated with greater symptom severity and illness characteristics suggestive of greater underlying risk, but not other demographic characteristics than age. Risk for recurrence appeared to be distinct from chronic depression. A subset of chronic first episode patients may lack the capacity to remit and may therefore be distinct from those with recurrent episodes.

Adolescent↗
PubMed2005

Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.

The activity of the presynaptic dopamine (DA) transporter (DAT) is critical in mediating the magnitude and duration of dopaminergic signaling in the brain. Multiple genetic studies have found an association between attention deficit hyperactivity disorder (ADHD) and a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'VNTR) of the hDAT gene (SLC6A3), however none of these studies examined the hDAT coding region for polymorphisms. Thus, we sought evidence of polymorphisms in hDAT, focusing on the coding region and splice junctions, utilizing genomic DNA from children diagnosed with ADHD. Two separate ADHD cohorts (N=70 and N=42) were screened and sampled for both status of the 3'VNTR and for common/novel genomic variants. We found evidence of increased DAT variation in African-American subjects as well as in predominantely hyperactive-impulsive probands. Cumulatively, multiple hDAT sequence variants were identified, including five novel variants, as well as one nonsynonymous single nucleotide polymorphism (SNP), converting Ala559 to Val (A559V). A559V was identified in two Caucasian male siblings with ADHD and both subjects were homozygous for the ADHD-associated, 10-repeat 3'VNTR allele. Interestingly, the A559V variant was previously identified in a subject with bipolar disorder [. Molecular Psychiatry 5, 275], a psychiatric disorder that has a significant number of overlapping symptoms with ADHD.

Adolescent↗
PubMed2005

Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase.

Human serotonin [5-hydroxytryptamine (5-HT)] transporters (hSERT, 5HTT, and SLC6A4) inactivate 5-HT after release and are prominent targets for therapeutic intervention in mood, anxiety, and obsessive-compulsive disorders. Multiple hSERT coding variants have been identified, although to date no comprehensive functional analysis of these variants has been reported. We transfected hSERT or 10 hSERT coding variants and examined total and surface protein expression, antagonist recognition, and transporter modulation by posttranslational, regulatory pathways. Two variants, Pro339Leu and Ile425Val, demonstrated significant changes in surface expression supporting alterations in 5-HT transport capacity (V(max)). Regardless of basal transport activity, all SERT variants displayed a capacity for rapid, phorbol ester-triggered down-regulation. Remarkably, five variants (Thr4Ala, Gly56Ala, Glu215Lys, Lys605Asn, and Pro612Ser) demonstrated no capacity for 5-HT uptake stimulation after acute protein kinase G (PKG)/p38 mitogen-activated protein kinase (MAPK) activation. Epstein-Barr virus (EBV)-transformed lymphocytes natively expressing the most common of these variants (Gly56Ala) exhibited a similar loss of 5-HT uptake stimulation by PKG/p38 MAPK activators. HeLa cells transfected with the Gly56Ala variant demonstrated elevated basal phosphorylation and, unlike hSERT, could not be further phosphorylated after 8-bromo cGMP (8BrcGMP) treatments. These studies reveal cellular phenotypes associated with naturally occurring human SERT coding variants and suggest that altered transporter regulation by means of PKG/p38 MAPK-linked pathways may influence risk for disorders attributed to compromised 5-HT signaling.

Cyclic GMP-Dependent Protein Kinases↗
PubMed2005

Cognitive therapy vs medications in the treatment of moderate to severe depression.

BACKGROUND: There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy's effects in this population. OBJECTIVE: To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial. DESIGN: Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60). SETTING: Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn. PATIENTS: Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder. INTERVENTIONS: Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy. MAIN OUTCOME MEASURE: The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission. RESULTS: At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site x treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction. CONCLUSION: Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.

Adult↗
PubMed2005

Prevention of relapse following cognitive therapy vs medications in moderate to severe depression.

BACKGROUND: Antidepressant medication prevents the return of depressive symptoms, but only as long as treatment is continued. OBJECTIVES: To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication. DESIGN: Patients who responded to CT in a randomized controlled trial were withdrawn from treatment and compared during a 12-month period with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal. Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a subsequent 12-month naturalistic follow-up. SETTING: Outpatient clinics at the University of Pennsylvania and Vanderbilt University. PATIENTS: A total of 104 patients responded to treatment (57.8% of those initially assigned) and were enrolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to severe depression. INTERVENTIONS: Patients withdrawn from CT were allowed no more than 3 booster sessions during continuation; patients assigned to continuation medication were kept at full dosage levels. MAIN OUTCOME MEASURES: Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression or Hamilton Depression Rating Scale scores of 14 or higher during the continuation phase. Recurrence was defined in a comparable fashion during the subsequent naturalistic follow-up. RESULTS: Patients withdrawn from CT were significantly less likely to relapse during continuation than patients withdrawn from medications (30.8% vs 76.2%; P = .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%; P = .20). There were also indications that the effect of CT extends to the prevention of recurrence. CONCLUSIONS: Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication.

Adult↗
PubMed2005

Do venlafaxine XR and paroxetine equally influence negative and positive affect?

BACKGROUND: We assessed the therapeutic effects of venlafaxine XR and paroxetine on mood and anxiety symptoms derived from the tripartite model of mood. We hypothesized that the two antidepressants would have largely similar effects on symptoms of negative affect because both agents influence serotonergic systems. However, based on evidence indicating linkages between catecholaminergic activity and the emotional dimension of positive affect, we hypothesized that the catecholaminergic effects of venlafaxine XR would yield particularly pronounced effects on symptoms of positive affect. METHODS: Twenty depressed outpatients were randomly assigned to treatment with either venlafaxine XR (225 mg/day) or paroxetine (30 mg/day) during a 12-week treatment trial. Weekly mood ratings were collected using the Mood and Anxiety Symptom Questionnaire [Watson, D., Clark, L.A., Weber, K., Assenheimer, J.S., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J. Abnorm. Psychol. 104 (1), 15-25] [Watson, D., Weber, K., Assenheimer, J.S., Clark, L.A., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychol. 104 (1), 3-14]. RESULTS: Consistent with predictions, analyses revealed that there were no significant differences between venlafaxine XR and paroxetine on measures of negative affect. However, contrary to predictions, the two medications produced similar changes on measures of positive affect. LIMITATIONS: Replication and extension using a larger sample size are mandated. CONCLUSIONS: These preliminary results suggest that two antidepressants that appear to have dissimilar mechanisms of action may nevertheless have similar effects on the positive and negative affective components of depression. Alternatively, paroxetine may have a clinically relevant noradrenergic effect at the dose tested.

Adult↗
PubMed2005

Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features.

BACKGROUND: This study evaluated the clinical and sociodemographic features associated with various degrees of concurrent comorbidity in adult outpatients with nonpsychotic major depressive disorder (MDD). METHODS: Outpatients enrolled in the STAR*D trial completed the Psychiatric Diagnostic Screening Questionnaire (PDSQ). An a priori 90% specificity threshold was set for PDSQ responses to ascertain the presence of 11 different concurrent DSM-IV Axis I disorders. RESULTS: Of 1376 outpatients, 38.2% had no concurrent comorbidities, while 25.6% suffered one, 16.1% suffered two, and 20.2% suffered three or more comorbid conditions. Altogether, 29.3% met threshold for social anxiety disorder, 20.8% for generalized anxiety disorder, 18.8% for posttraumatic stress disorder, 12.4% for bulimia, 11.9% for alcohol abuse/dependence, 13.4% for obsessive-compulsive disorder, 11.1% for panic disorder, 9.4% for agoraphobia, 7.3% for drug abuse/dependence, 3.7% for hypochondriasis, and 2.2% for somatoform disorder. Those with more concurrent Axis I conditions had earlier ages at first onset of MDD, longer histories of MDD, greater depressive symptom severity, more general medical comorbidity (even though they were younger than those with fewer comorbid conditions), poorer physical and mental function, health perceptions, and life satisfaction; and were more likely to be seen in primary care settings. LIMITATIONS: Participants had to meet entry criteria for STAR*D. Ascertainment of comorbid conditions was not based on a structured interview. CONCLUSIONS: Concurrent Axis I conditions (most often anxiety disorders) are very common with MDD. Greater numbers of concurrent comorbid conditions were associated with increased severity, morbidity, and chronicity of their MDD.

Adult↗
PubMed2005

Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.

BACKGROUND: This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination. METHOD: The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies. CONCLUSIONS: The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.

Adult↗