Brian A. Palmer

Serial infusions of low-dose ketamine for major depression

Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy. Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions. Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period. Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.

Potential Risks of Poorly Monitored Ketamine Use in Depression Treatment.

At the time of his initial presentation to a tertiary medical center in 2012, “Mr. A” was a 52-year-old divorced man with a 30-year history of recurrent major depressive disorder, persistent depressive disorder, and a remote history of outpatient treatment for alcohol use disorder as a young adult. His first episode of major depression occurred at age 22 in association with a suicide attempt (he jumped off a four-story building) and subsequent hospitalization. Mr. A’s medical history was significant for corrected hypothyroidism. The prospective course of illness encompassed four subsequent psychiatric admissions at our medical center, annually from 2012 to 2014, illustrating clear treatment-resistant depression and a reemerging pattern of substance misuse (alcohol, benzodiazepines, and ketamine). Mr. A’s admission in the summer of 2012 focused on consultation for depression and consideration of ECT. Prior medication trials of optimal dose and duration included trazodone, escitalopram, bupropion, and mirtazapine with lamotrigine and aripiprazole augmentation strategies. Mr. A reported negligible alcohol consumption (a single drink on rare occasions). He received seven bilateral ECT treatments, and his symptoms improved; his score on the Hamilton Depression Rating Scale declined from 37 on admission to 8 at discharge. He was discharged after 18 days on mirtazapine monotherapy with recommendations to maximize his dosing of mirtazapine and to add lithium for augmentation following his ECT course. HereceivedthreeadditionalECTtreatmentspriortoself

Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders.

The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC⩾0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged.

Acute suicidal affective disturbance: factorial structure and initial validation across psychiatric outpatient and inpatient samples

BACKGROUND A new clinical entity, Acute Suicidal Affective Disturbance (ASAD), was recently proposed to characterize rapid-onset, acute suicidality including the cardinal symptom of behavioral intent. This study examines the proposed ASAD criteria factor-analytically and in relation to correlates of suicidal behavior and existing psychiatric disorders in samples of psychiatric outpatients and inpatients. METHODS Two samples of psychiatric outpatients (N=343, aged 18-71 years, 60.6% female, 74.9% White) and inpatients (N=7,698, aged 15-99 years, 57.2% female, 87.8% White) completed measures of their ASAD symptoms and psychological functioning. RESULTS Across both samples, results of a confirmatory factor analysis supported the unidimensional nature of the ASAD construct. Additionally, results provided evidence for the convergent and discriminant validity of ASAD, demonstrating its relation to, yet distinction from, other psychiatric disorders and correlates of suicide in expected ways. Importantly, ASAD symptoms differentiated multiple attempters, single attempters, and non-attempters, as well as attempters, ideators, and non-suicidal patients, and was an indicator of past suicide attempts above and beyond symptoms of depression and other psychiatric disorders. LIMITATIONS This study utilized cross-sectional data and did not use a standardized measure of ASAD. CONCLUSIONS ASAD criteria formed a unidimensional construct that was associated with suicide-related variables and other psychiatric disorders in expected ways. If supported by future research, ASAD may fill a gap in the current diagnostic classification system (DSM-5) by characterizing and predicting acute suicide risk.

Continuation phase intravenous ketamine in adults with treatment-resistant depression.

BACKGROUND Little is known about the antidepressive effects of repeated intravenous ketamine infusions beyond the acute phase of treatment in patients with refractory depression. METHODS Twelve subjects with treatment-resistant non-psychotic unipolar or bipolar major depression and suicidal ideation were given repeated (up to 6) thrice-weekly acute-phase intravenous infusions of ketamine (0.5mg/kg, administered over 100min). Those who remitted during acute-phase treatment received continuation-phase treatment that consisted of 4 weekly ketamine infusions, followed by 4 weeks of post-continuation phase follow-up (during which no further ketamine infusions were administered). Clinical measures were assessed at baseline, at 24h following each infusion, at the last acute-phase observation, and during continuation and post-continuation follow-up (acute phase remitters only). RESULTS Of the 12 enrollees, 5 (41.7%) remitted and 7 (58.3%) responded to ketamine treatment during the acute-phase. All five subjects who remitted during the acute-phase experienced further depressive symptom improvement during continuation-phase treatment. Four subjects lost remission status during the post-continuation phase, but all were still classified as positive treatment responders at the end of the post-continuation phase. Adverse effects were generally mild and transient during acute- and continuation-phase treatment; however, one subject developed behavioral outbursts and suicide threats during follow-up while hospitalized, and one subject died by suicide several weeks after the end of follow-up. LIMITATIONS This was an uncontrolled feasibility study with a small sample size. CONCLUSIONS The continuation-phase administration of ketamine at weekly intervals to patients with treatment-resistant depression who remitted during acute-phase ketamine treatment can extend the duration of depressive symptom remission. The antidepressive effect of ketamine persisted for several weeks after the end of continuation-phase treatment. Our results highlight the need for close monitoring of subjects who are at high baseline risk for suicide but do not respond clinically to ketamine. CLINICALTRIALS. GOV IDENTIFIER NCT02094898.

Clinical Risk Factors and Serotonin Transporter Gene Variants Associated With Antidepressant-Induced Mania

INTRODUCTION Identifying clinical and genetic risk factors associated with antidepressant-induced mania (AIM) may improve individualized treatment strategies for bipolar depression. METHOD From 2009 to 2012, bipolar depressed patients, confirmed by DSM-IV-TR-structured interview, were screened for AIM. An AIM+ case was defined as a manic/hypomanic episode within 60 days of starting or changing dose of antidepressant, while an AIM- control was defined as an adequate (≥ 60 days) exposure to an antidepressant with no associated manic/hypomanic episode. 591 subjects (205 AIM+ and 386 AIM-) exposed to an antidepressant and a subset of 545 subjects (191 AIM+ and 354 AIM-) treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) were used to evaluate the association of AIM with phenotypic clinical risk factors previously published. 295 white subjects (113 AIM+ cases, 182 AIM-controls) were genotyped for 3 SLC6A4 variants: the 5-HTTLPR, single nucleotide polymorphism (SNP) rs25531, and the intron 2 variable number of tandem repeats (VNTR). Tests of association with AIM were performed for each polymorphism and the haplotype. RESULTS The only clinical risk factors associated with AIM in the overall and the SSRI + SNRI analysis was bipolar I subtype. The S allele of 5-HTTLPR was not significantly associated with AIM; however, a meta-analysis combining this sample with 5 prior studies provided marginal evidence of association (P = .059). The L-A-10 haplotype was associated with a reduced risk of AIM (P = .012). DISCUSSION Narrowly defined, AIM appears to be at greatest risk for bipolar I patients. Our haplotype analysis of SLC6A4 suggests that future pharmacogenetic studies should not only focus on the SLC6A4 promotor variation but also investigate the role of other variants in the gene.

Gender differences in the association of agitation and suicide attempts among psychiatric inpatients

OBJECTIVE To determine if the relationship of agitation with suicide ideation and suicide attempts differed between men and women. METHOD Self-reported severity of agitation and other suicide risk factors was obtained from 7698 consecutive patients during admission for inpatient psychiatric treatment during a 5-year period. RESULTS Agitation was highest among men with a history of suicide attempts. Agitation was significantly associated with frequency of suicide ideation and history of suicide attempt, but the gender-by-suicide interaction was only significant as a predictor of suicide attempt history. For men, agitation was associated with significantly increased risk for suicide attempt, but for women, agitation was not associated with risk for suicide attempt history. Results were unchanged when analyses were repeated among the subgroup of patients with suicide ideation. CONCLUSIONS Agitation is associated with history of suicide attempt among male but not female psychiatric inpatients. Agitation differentiates between those men who have only thought about suicide and those who have made suicide attempts.

Predictors of medical school clerkship performance: a multispecialty longitudinal analysis of standardized examination scores and clinical assessments

BackgroundEvidence suggests that poor performance on standardized tests before and early in medical school is associated with poor performance on standardized tests later in medical school and beyond. This study aimed to explore relationships between standardized examination scores (before and during medical school) with test and clinical performance across all core clinical clerkships.MethodsWe evaluated characteristics of 435 students at Mayo Medical School (MMS) who matriculated 2000–2009 and for whom undergraduate grade point average, medical college aptitude test (MCAT), medical school standardized tests (United States Medical Licensing Examination [USMLE] 1 and 2; National Board of Medical Examiners [NBME] subject examination), and faculty assessments were available. We assessed the correlation between scores and assessments and determined USMLE 1 cutoffs predictive of poor performance (≤10th percentile) on the NBME examinations. We also compared the mean faculty assessment scores of MMS students vs visiting students, and for the NBME, we determined the percentage of MMS students who scored at or below the tenth percentile of first-time national examinees.ResultsMCAT scores correlated robustly with USMLE 1 and 2, and USMLE 1 and 2 independently predicted NBME scores in all clerkships. USMLE 1 cutoffs corresponding to poor NBME performance ranged from 220 to 223. USMLE 1 scores were similar among MMS and visiting students. For most academic years and clerkships, NBME scores were similar for MMS students vs all first-time examinees.ConclusionsMCAT, USMLE 1 and 2, and subsequent clinical performance parameters were correlated with NBME scores across all core clerkships. Even more interestingly, faculty assessments correlated with NBME scores, affirming patient care as examination preparation. USMLE 1 scores identified students at risk of poor performance on NBME subject examinations, facilitating and supporting implementation of remediation before the clinical years. MMS students were representative of medical students across the nation.

How does active substance use at psychiatric admission impact suicide risk and hospital length of stay

ABSTRACT Despite their high prevalence, little is known about the effects of substance use disorders and active substance use on the suicide risk or length-of-stay of psychiatric inpatients. This study examines the relationship between active substance use at the time of psychiatric hospitalization and changes in suicide risk measures and length-of-stay. Admission and discharge ratings on the Suicide Status Form-II-R, diagnoses, and toxicology data from 2,333 unique psychiatric inpatients were examined. Data for patients using alcohol, tetrahydrocannabinol, methamphetamines, cocaine, benzodiazepines, opiates, barbiturates, phencyclidine, and multiple substances on admission were compared with data from 1,426 admissions without substance use. Patients with substance use by toxicology on admission had a 0.9 day shorter length-of-stay compared to toxicology-negative patients. During initial nurse evaluation on the inpatient unit, these patients reported lower suicide measures (i.e., suicidal ideation frequency, overall suicide risk, and wish-to-die). No significant between-group differences were seen at discharge. Patients admitted with a substance use disorder diagnosis had a 1.0 day shorter length-of-stay than those without, while those with a substance use disorder diagnosis and positive toxicology reported the lowest measures of suicidality on admission. These results remained independent of psychiatric diagnosis. For acute psychiatric inpatients, suicide risk is higher and length-of-stay is longer in patients with substance use disorders who are NOT acutely intoxicated compared with patients without a substance use disorder. Toxicology-positive patients are less suicidal on admission and improve faster than their toxicology-negative counterparts. This study gives support to the clinical observation that acutely intoxicated patients may stabilize quickly with regard to suicidal urges and need for inpatient care.

Psychosis or Obsessions? Clozapine Associated with Worsening Obsessive-Compulsive Symptoms

One underrecognized adverse event of clozapine is the emergence or worsening of obsessive-compulsive symptoms (OCS). OCS, particularly violent thoughts, can be inaccurately described as psychosis and result in a misdiagnosis. We report a case of a 42-year-old man, initially diagnosed with schizoaffective, who was placed on clozapine for the management of “violent delusions.” However, clozapine led to a worsening of these violent thoughts resulting in suicidal ideation and hospitalization. After exploration of the intrusive thoughts and noting these to be egodystonic, clearly disturbing, and time consuming, an alternative diagnosis of obsessive-compulsive disorder (OCD) was made. Clozapine was inevitably discontinued resulting in a significant reduction of the intrusive thoughts without emergence of psychosis or adverse events. While an overlapping phenomenology between OCD and psychotic disorders has been described, clozapine and other antiserotonergic antipsychotics have been implicated with the emergence or worsening of OCS. Unique to our case is that the patients obsessions had been treated as psychosis leading to the inadequate treatment of his primary illness, OCD. This case highlights the potential for OCD to masquerade as a psychotic disorder and reminds clinicians that clozapine may worsen OCS.