Introduction
Treatment Resistant Depression (TRD) occurs in up to 30% of patients with Major Depressive Disorder (MDD). New treatments are clearly needed and there is a burgeoning interest in novel ...agents including ketamine. While ketamine in various formulations has been demonstrated to have a robust antidepressant effect there is a lack of evidence-based psychotherapies specifically designed for combination use.
Objectives
We hypothesize that the combination of “Almond TherapyTM” with intranasal ketamine will result in a statistically significantly better outcome as demonstrated by a greater reduction in MADRS scores and/or response rates and/or remission rates in TRD patients compared with those who receive esketamine plus TAU. Secondary outcome measures include PHQ-9, GAD-7, PCL-5, Asssessment of Quality of Life - 8D (AQOL-8D), and Rosenberg Self-Esteem Scale.
Methods
We have developed a research protocol combining a unique and specifically-designed, multi-modal psychotherapy program, “Almond TherapyTM”, with intranasal esketamine in a randomized, controlled, single-blind 28-day study. The therapy utilizes an individualized, evidence-informed approach for each participant consisting of a number of modules selected using a shared decision-making process determined at the first study visit. This uniquely tailored approach ensures that the chosen modules are personally meaningful to the participant, and thus, promotes therapeutic adherence. The proprietary therapy combines elements of cognitive behavioral therapy (CBT), trauma focused-CBT, Dialectical Behavioral Therapy (DBT), and mindfulness, together with biofeedback. In addition to in-clinic sessions, participants also receive standardized remote therapy sessions by trained therapists.
Results
Patient recruitment and enrolment has begun. Interim results are anticipated.
Conclusions
This study is the first examination of the potential additional clinical benefit of adding a specific therapy program to existing intranasal esketamine treatment. If demonstrated to be of clinical benefit then further studies may potentially provide comparison to other therapy programs and in conjunction with other agents.
Disclosure of Interest
P. Chue Shareolder of: Zylorion, P. Silverstone Shareolder of: Zylorion, Employee of: Zylorion, T. Hillier Shareolder of: Zylorion, Employee of: Zylorion, S. Rizvi: None Declared, S. Phillips Shareolder of: Zylorion, Employee of: Zylorion, L.-A. Langkaas Employee of: Zylorion, K. Davidson Employee of: Zylorion, M. Brown: None Declared, J. Chue: None Declared
Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission ...reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.
A subset of patients with comorbid major depressive disorder and generalized anxiety disorder (GAD) was examined from a double-blind. placebo-controlled study comparing the efficacy and safety of ...venlafaxine extended release (XR) and fluoxetine.
From a total of 368 patients, 92 patients meeting DSM-IV criteria for major depressive disorder who also had comorbid GAD were identified. The comparison group comprised 276 evaluable noncomorbid patients. Patients received venlafaxine XR (75-225 mg/day), fluoxetine (20-60 mg/day), or placebo for 12 weeks. Efficacy evaluations included Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions (CGI) scale.
By the final assessment at week 12, comorbid patients in the venlafaxine XR group, but not in the fluoxetine group, showed a significantly greater decrease than those in the placebo group in the primary efficacy variables of mean HAM-D and HAM-A total scores (p < .05, pairwise comparison). In comorbid patients, significant pairwise differences were noted between venlafaxine XR and placebo at week 12 for the secondary variables of HAM-D anxiety-somatization and retardation factors, HAM-D depressed mood item. HAM-A psychic anxiety factor, the Hospital Anxiety and Depression scale (HAD) anxiety subscale score, and the Covi Anxiety Scale score. Fluoxetine was significantly different from placebo only on the HAD depression subscale score. Response, defined as > or = 50% decrease in symptoms score, was achieved in 66% and 59% of the comorbid patients for HAM-D and HAM-A, respectively, in the venlafaxine XR group at week 12. This response was higher than that seen with fluoxetine (52% and 45%) or placebo (36% and 24%). Onset of efficacy appeared to be slower in comorbid than in noncomorbid patients.
This is the first evidence from a controlled study of the effectiveness of pharmacotherapy in patients with comorbid major depressive disorder and GAD. The delayed improvement in comorbid patients compared with noncomorbid patients suggests that a longer treatment period may be necessary in comorbid patients.
The aim of the present study was to determine the prevalence of psychiatric disorders in acutely ill medical inpatients. A total of 313 consecutively admitted patients were interviewed using a ...semistructured psychiatric interview. Diagnoses were made according to DSM-IV diagnostic criteria during two time periods, the 7 days following admission and the month prior to admission. The results showed that 85 patients (27.2%) received a DSM-IV diagnosis, with several patients having comorbid diagnoses. Major depressive disorder was present in 16 patients (5.1%), most of whom also had major depressive disorder in the month prior to admission. This prevalence rate is above that of the general population (1.2% to 2.8%), but less than that reported in most previous studies (20% to 40%). Forty-three patients (13.7%) had an adjustment disorder, 18 patients (5.8%) had an anxiety disorder, and 17 patients (5.4%) had either alcohol dependence or abuse. Nurses were more proficient than medical staff at identifying patients who had received a DSM-IV diagnosis, recognizing 61% of cases compared with 41% for medical staff.
Decreased cognitive ability is a significant problem in schizophrenia, and it has been proposed that augmentation of antipsychotics with 5HT(1A) receptor agonists may improve cognitive performance. ...Clinical studies have been mixed but there have been no studies specifically examining the effects of combining the atypical antipsychotic quetiapine with the 5HT(1A) receptor partial agonist, buspirone on monoamine release. This is of interest given previous evidence that monoamine release can alter cognition in schizophrenia. In the present study we measured in vivo levels of monoamines in the frontal cortex of Sprague Dawley rats and examined if buspirone (2.5 mg/kg i.p.), altered monoamine release both when given alone and when combined with quetiapine (10 mg/kg i.p.). We found that serotonin levels were not altered by either drug, either alone or in combination. In contrast, both buspirone and quetiapine monotherapy significantly increased release of noradrenaline (112 and 160% respectively) and dopamine (169 and 191% respectively) compared to controls. However, there were no additional increases in in vivo monoamine release when the combination of these drugs were given. One possible explanation for these negative findings could be that the intrinsic 5HT(1A) agonist activity of quetiapine on its own is of such significance that it is not further enhanced by buspirone. These findings do not support clinical studies combining buspirone and quetiapine, if these were to be used on the basis of enhanced monoamine neurotransmission. These findings may also have implications for the atypical antipsychotic drugs in development which combine dopamine D(2) antagonism with 5HT(1A) partial agonism.
This was an 8-week, multicenter, open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada. Inpatients or outpatients aged ...18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression (HAM-D-21) score of 2 > or = 18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant. Treatment with venlafaxine was started at 37.5 mg twice daily, and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator's assessment of clinical response and tolerability. Of the 159 patients enrolled, 152 were evaluable for efficacy. The mean daily venlafaxine dose was 260 mg/day. The mean HAM-D-21 score decreased by 52%, and the mean Montgomery-Asberg Depression Rating Scale score decreased by 50% from baseline to day 56. A response (50% improvement from baseline) was achieved by 58% of patients on the HAM-D-21, and a remission (> or = 75% improvement in the HAM-D-21) was observed in 28% at day 56. By day 56, 88% of patients had improved from baseline on the Clinical Global Impression Improvement scale. Only 8% of the patients discontinued for adverse events. The most common adverse events were headache, insomnia, nausea, constipation, diaphoresis, and xerostomia. In conclusion, these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression.
The present study was designed to determine if the mood stabilizers, lithium and valproate, have common effects on concentrations of amino acid neurotransmitters which may be related to their ...mechanisms of action. Two separate groups of rats were administered therapeutic doses of lithium, sodium valproate, or saline for 2 weeks. Whole brain extracts were then examined using either high-field
1H NMR spectroscopy or HPLC. Both drugs decreased whole brain concentrations of aspartate, glutamate, and taurine while brain concentrations of γ-aminobutyric acid (GABA) and alanine decreased following chronic sodium valproate administration but not following chronic lithium administration. These findings indicate that lithium and sodium valproate share common effects on the concentrations of certain amino acid neurotransmitters in whole brain which may be related to their mechanisms of action in bipolar disorder.
Recent studies have shown that the use of subscales derived from the Hamilton Depression (HAM-D) rating scale are just as reliable and enhance sensitivity for detecting response and remission after ...antidepressant treatment. The purpose of the present study was to determine if the responses on two items of the HAM-D scale, Depressed Mood (item 1) and Psychic Anxiety (item 10), were predictive of remission of depression in placebo-controlled studies following treatment with venlafaxine or selective serotonin reuptake inhibitors (SSRIs). Data from eight active- and placebo-controlled studies consisting of 2027 subjects who met the DSM-III-R/-IV criteria for major depressive disorder were analysed. Three treatment groups were compared: venlafaxine (n =843), SSRI (either fluoxetine, paroxetine or fluvoxamine, n=743) and placebo (n=441). Treatment duration was 6-8 weeks. Patients who scored zero on the depressed mood and the psychic anxiety items of the HAM-D17 scale were designated as responders. These two scores were also combined to create an Absence of Depressive and Anxious Mood (ADAM) score. Between-group rate comparisons in outcome measures were carried out using Fisher's exact test and logistic regression models. Venlafaxine treatment improved depressed mood, psychic anxiety and ADAM scores after 2 weeks with greater efficacy than treatment with SSRIs or placebo. ADAM scores could also predict the odds ratio of a patient achieving a clinical remission (defined as total HAM-D17 score </= 7). The present results demonstrate that using just two items of the HAM-D17 can be very useful in assessing treatment response, differentiating between treatment groups and predicting remission rates.
The discovery of multiple subtypes of the serotonin 5-HT receptor has generated enormous interest over the past few years. Possibly the most exciting, in terms of psychiatric clinical practice, ...appeared to be the 5-HT3 receptor. Early animal studies suggested that the 5-HT3 receptor antagonists, in addition to their well recognised antiemetic use, might be clinically useful in a number of areas. These included anxiety disorders, psychotic disorders, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, the treatment of pain and the treatment of irritable bowel syndrome. With the exception of antiemetic actions, this review examines these potential therapeutic areas carefully, paying particular attention not only to the animal literature, but to the clinical studies which have resulted from these initial findings. Unfortunately, studies in many of these therapeutic areas have not lived up to their initial promise. Indeed, no clinical studies have yet clearly demonstrated the usefulness of 5-HT3 receptor antagonists in the treatment of CNS disorders. Nonetheless, in view of the absence of published results from double-blind, placebo-controlled studies in many of these therapeutic areas, further research would be useful in confirming the effectiveness, or otherwise, of this group of compounds.
The Hospital Anxiety and Depression scale (HAD) is a brief questionnaire which was designed to indicate the likely presence of a depressive disorder in medically ill patients. However, more recently ...it has been used in several research studies to determine the presence of depression in both medical and psychiatric patients. The aim of the present study was to validate the usefulness of the HAD when used in this way. The HAD was compared to DSM-III-R diagnoses of major depressive disorder in 153 medical inpatients and 147 psychiatric out-patients. In both groups the sensitivity of the HAD was between 80 and 100% using the cut-off point of 8. However, the positive predictive value (PPV) of the HAD was only 17% in medical patients and 29% in psychiatric patients. Changing the cut-off point for depression or using the total HAD score did not significantly improve the PPV. These findings suggest that the HAD does not accurately determine the presence of DSM-III-R major depressive disorder in medical or psychiatric patients, and should not be used as a research instrument for this purpose. Nonetheless, the HAD should still be used for its original purpose, namely as a clinical indicator as to the possibility of a depressive disorder.
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