The effects of ketamine on typical and atypical depressive symptoms.

OBJECTIVE: Ketamine's effects on different dimensions of depressive symptomatology, including typical/melancholic and atypical depression, remain largely unknown. This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). METHODS: Data from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar depression were pooled from three separate, double-blind, placebo-controlled, crossover studies investigating ketamine's efficacy in depression. MDD participants were unmedicated; bipolar participants received therapeutic-dose lithium or valproate. Clinical symptoms were collected preinfusion and up to 14 days postinfusion. Effect sizes were calculated for days 1 and 3 postinfusion. The primary measures of interest for this exploratory analysis were total MADRS, MADRS5, and SAS scores. Individual symptoms were also analyzed in an exploratory manner. RESULTS: Scores improved significantly at Day 1 postinfusion (MADRS: Cohen's d = 0.64; MADRS5: Cohen's d = 0.61; SAS: Cohen's d = 0.41) and continued to be significantly improved over placebo at Day 3 (MADRS: Cohen's d = 0.49; MADRS5: Cohen's d = 0.43; SAS: Cohen's d = 0.39). Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. CONCLUSION: Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former.

Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder.

Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.

The role of adipokines in the rapid antidepressant effects of ketamine.

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines-adiponectin, resistin and leptin-as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg-1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine's antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine's anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants.

The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression-the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm-as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.

Translational research in bipolar disorder: emerging insights from genetically based models.

Bipolar disorder (BPD) is characterized by vulnerability to episodic depression and mania and spontaneous cycling. Because of marked advances in candidate-gene and genome-wide association studies, the list of risk genes for BPD is growing rapidly, creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment. However, genetic findings are associated with major unresolved issues, including whether and how risk variance leads to behavioral abnormalities. Although animal studies are key to resolving these issues, consensus is needed regarding how to define and monitor phenotypes related to mania, depression and mood swing vulnerability in genetically manipulated rodents. In this study we discuss multiple facets of this challenging area, including theoretical considerations, available tests, limitations associated with rodent behavioral modeling and promising molecular-behavioral findings. These include CLOCK, glycogen synthase kinase 3beta (GSK-3beta), glutamate receptor 6 (GluR6), extracellular signal-regulated kinase-1 (ERK1), p11 (or S100A10), vesicular monoamine transporter 2 (VMAT2 or SLC18A2), glucocorticoid receptors (GRs), Bcl-2-associated athanogene-1 (BAG1) and mitochondrial DNA polymerase-gamma (POLG). Some mutant rodent strains show behavioral clusters or activity patterns that cross-species phenocopy objective/observable facets of mood syndromes, and changes in these clustered behaviors can be used as outcome measures in genetic-behavioral research in BPD.

Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces personnel.

BACKGROUND: In both psychiatrically ill and psychiatrically healthy adults, the connection between health and individuals' height and weight has long been examined. Specifically, research on the idea that individuals with certain body types were prone to particular psychiatric diseases has been explored sporadically for centuries. The hypothesis that psychiatrically ill individuals were shorter and weighed less than psychiatrically healthy counterparts would correspond with the neurodevelopmental model of psychiatric disease. METHOD: To evaluate possible links between psychiatric illness and physique, the height, weight and BMI of 7514 patients and 85,940 controls were compared. All subjects were part of the National Collaborative Study of Early Psychosis and Suicide (NCSEPS). Patients were US military active duty personnel hospitalized for either bipolar disorder, major depressive disorder, or schizophrenia and controls were psychiatrically-healthy US military active duty personnel matched for date of entry into the service. RESULTS: No consistent differences in height, weight or BMI were found between patients and controls, or between patient groups. Some weak ANOVA differences were found between age at the time of entering active duty and weight, as well as BMI, but not height. CONCLUSIONS: Unlike most previous studies that have looked at the links between height and psychiatric illness, this study of the NCSEPS cohort found that, at entry into the US Armed Forces, there were no consistent decreases in height for patients with bipolar disorder, major depressive disorder or schizophrenia compared with a large control group. Furthermore, there were no consistent differences for weight or BMI.

Lithium revisited: savings brought about by the use of lithium, 1970-1991.

BACKGROUND: Recent estimates of the cost of manic-depressive illness totaled roughly $45 billion in 1991. Using data from the Epidemiological Catchment Area (ECA) study, this study estimates the savings brought about by the use of lithium between 1970 and 1991. METHODS: Total savings are the difference between estimated actual costs and projected costs had lithium never been introduced. Actual yearly costs were interpolated from data for 1970 and 1991, and projected costs were obtained by adjusting 1970 costs with Consumer Price Index (CPI) and population inflaters. All costs for 1970 were obtained using methods almost identical to those used to calculate the 1991 costs of manic-depressive illness, presented in a previous publication. All savings are presented in 1991 dollars. RESULTS: Between 1970 and 1991, lithium saved over $170 billion, or roughly over $8 billion per year. Approximately $15 billion in direct costs, which included inpatient and outpatient care as well as research, was saved between 1970 and 1991. The savings are more dramatic for indirect costs, which include the lost productivity of wage-earners, homemakers, family caregivers, and individuals who are in institutions or who committed suicide; these totaled roughly $155 billion. CONCLUSIONS: Our results suggest that, although manic-depressive illness is still costly, lithium has been tremendously successful in treating the illness, and has provided enormous financial savings in the process.

The long-term effects of placebo in patients with chronic schizophrenia.

BACKGROUND: It has been hypothesized that placebo periods may increase long-term morbidity for patients with schizophrenia. In this study, the long-term effect of a placebo period was evaluated in a group of relatively treatment-refractory patients with chronic schizophrenia. METHODS: This retrospective study examined behavioral rating scores for 127 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. Patients were rated daily with the Psychiatric Symptom Assessment Scale (PSAS), an extended and anchored version of the Brief Psychiatric Rating Scale (BPRS). At the end of the placebo phase, most patients were placed on haloperidol. Pre-placebo baseline PSAS ratings were compared with, first, discharge ratings and second, post-placebo ratings. To determine expected variability in the course of illness, patients in the placebo group were compared with patients hospitalized during the same time period, but who did not enter the placebo study. RESULTS: By discharge, ratings for placebo patients had returned to baseline. Post-placebo ratings were quite variable. Although many of the placebo patients had returned to baseline by day 3 of the post-placebo phase, others had not returned to baseline by post-placebo day 42. PSAS Total Scores for patients who left the study early were no different at baseline, placebo, or through post-placebo day 35 compared with patients who completed the study. CONCLUSIONS: The results indicate that given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline, but that the speed with which they attain that recovery is highly variable.

Do antipsychotic medications decrease the risk of suicide in patients with schizophrenia?

The lifetime risk of suicide in persons with schizophrenia is much greater than that in the general population. The role of antipsychotic medications in decreasing suicide risk in schizophrenia has been little studied, and results often appear inconclusive and even confusing when issues such as dose-response effect are examined. Yet, evidence exists that both the traditional and newer antipsychotic medications reduce the risk of suicide and suicide attempts in schizophrenia. Because side effects are potentially significant risk factors in suicide, considerable incentive exists to examine whether newer antipsychotic agents that have a lower incidence of extrapyramidal side effects offer greater safety for this population.

The effects of early and sustained intervention on the long-term morbidity of schizophrenia.

By examining the literature concerning early intervention with antipsychotic medications, and how it affects long-term morbidity, this article will review the concept that early intervention with antipsychotic medications improves the long-term course of schizophrenia. It also looks at the potential long-term effects of discontinuing antipsychotic medications early in the course of schizophrenia. It appears that early intervention with antipsychotic medications decreases some of the long-term morbidity associated with schizophrenia. Some of the implications of this finding are discussed in the context of both clinical practice and clinical research.

First-episode schizophrenia. Early intervention and medication discontinuation in the context of course and treatment.

BACKGROUND: The concept that early intervention with antipsychotic medications improves the long-term course of schizophrenia is discussed. METHOD: This report reviews the literature concerning early intervention with antipsychotic medications for people with first episodes, and how it affects long-term morbidity. It also studies the effects of discontinuing antipsychotic medications on relapse for people with first episodes. RESULTS: Early intervention with antipsychotic medications appears to decrease the long-term morbidity of schizophrenia. CONCLUSIONS: Early intervention with antipsychotic medications should be encouraged for people experiencing their first episode of schizophrenia. This report proposes that studying the various phases of subject response to treatment can be helpful in elucidating when antipsychotic medications should be tapered or withdrawn.