Rapid and sustained improvement in treatment-refractory depression through use of acute intravenous ketamine and concurrent transdermal selegiline: A case series.

BACKGROUND: Treatment resistant depression is a significant source of morbidity and mortality. For patients having failed or unable to undergo the electroconvulsive therapy procedure few effective alternative treatments exist. METHODS: A case series is presented where six patients with treatment resistant depression failing both electroconvulsive therapy and oral antidepressants are concomitantly treated with short course intravenous ketamine and longer term selegiline transdermal system. RESULTS: All six patients experienced clinical improvement with intravenous ketamine, with resolution of suicidality, increased food intake, and commitment to treatment adherence. Five patients showed sustained improvement with the selegiline transdermal system. One patient discontinued selegiline after developing peripheral edema and palpitations. LIMITATIONS: This case series included only patients experiencing moderate to severe treatment resistant depression. Availability of long-term follow-up data not available in some cases. CONCLUSION: Intravenous ketamine with simultaneous administration of the selegiline transdermal system is one strategy for treating treatment resistant depression in patients having failed or unable to undergo the electroconvulsive therapy procedure.

Associations and Heritability of Auditory Encoding, Gray Matter, and Attention in Schizophrenia.

BACKGROUND: Auditory encoding abnormalities, gray-matter loss, and cognitive deficits are all candidate schizophrenia (SZ) endophenotypes. This study evaluated associations between and heritability of auditory network attributes (function and structure) and attention in healthy controls (HC), SZ patients, and unaffected relatives (UR). METHODS: Whole-brain maps of M100 auditory activity from magnetoencephalography recordings, cortical thickness (CT), and a measure of attention were obtained from 70 HC, 69 SZ patients, and 35 UR. Heritability estimates (h2r) were obtained for M100, CT at each group-difference region, and the attention measure. RESULTS: SZ patients had weaker bilateral superior temporal gyrus (STG) M100 responses than HC and a weaker right frontal M100 response than UR. Abnormally large M100 responses in left superior frontal gyrus were observed in UR and SZ patients. SZ patients showed smaller CT in bilateral STG and right frontal regions. Interrelatedness between 3 putative SZ endophenotypes was demonstrated, although in the left STG the M100 and CT function-structure associations observed in HC and UR were absent in SZ patients. Heritability analyses also showed that right frontal M100 and bilateral STG CT measures are significantly heritable. CONCLUSIONS: Present findings indicated that the 3 SZ endophenotypes examined are not isolated markers of pathology but instead are connected. The pattern of auditory encoding group differences and the pattern of brain function-structure associations differ as a function of brain region, indicating the need for regional specificity when studying these endophenotypes, and with the presence of left STG function-structure associations in HC and UR but not in SZ perhaps reflecting disease-associated damage to gray matter that disrupts function-structure relationships in SZ.

High Resource Utilization of Psychiatric Emergency Services by Methamphetamine Users.

Methamphetamine use has increased throughout the United States in recent years, and is historically prevalent in Hawai'i. This retrospective study aimed to determine the effect of methamphetamine use on emergency department (ED) resources, by examining visits to an emergency department (ED) in an urban hospital in Hawai'i from 2007 - 2011. The rate of patients who tested positive for amphetamine was measured and broken down by year. Primary outcomes included length of ED stay, the administration of medication or physical restraints for safety, and the rate of psychiatric hospitalization. Overall, 15.1% of drug-screened patients (N = 16,018) tested positive for amphetamines over the study period. Amphetamine-positive patients spent more time per visit on average in the ED, and were more likely to require medication and physical restraints, compared to amphetamine-negative patients. Amphetamine positive patients were admitted to inpatient psychiatry less frequently than negative-testing patients. In summary, there is higher resource utilization per psychiatric emergency service visit by amphetamine-positive patients; however if patients can be stabilized in the ED, the increased ED resources utilized may be offset by the reduced burden on inpatient facilities.

Simultaneous usage of dementia medications and anticholinergics among Asians and Pacific Islanders.

BACKGROUND: The simultaneous use of dementia medications and anticholinergic medications occurs frequently. Cholinesterase inhibitors and anticholinergic medications likely counteract one another, potentially exposing patients to medications with decreased benefit, more adverse effects, and higher cost of care. We identified the rate of concurrent prescriptions of cholinesterase inhibitors/memantine with anticholinergics in an urban hospital setting with a large Asian and Pacific Islander population. METHODS: This study is a retrospective review of patients hospitalized from 1 January 2006 to 31 December 2010 at a general hospital who simultaneously received US Food and Drug Administration-approved dementia medications (galantamine, rivastigmine, donepezil, and/or memantine) and anticholinergics. RESULTS: Overall, 304 patients receiving cholinesterase inhibitors/memantine also received anticholinergics. Of these patients, 64.1% were given high-potency anticholinergic medications, and 35.9% received medium-potency medications. Indications for the use of anticholinergic medication were urological (17.8%), gastrointestinal excluding nausea (32.6%), nausea (10.2%), psychiatric (7.9%), and other (31.6%). Asian patients received the combination of cholinesterase inhibitors/memantine and anticholinergics less frequently than Native Hawaiian or Caucasian patients (8.4% vs 12.2% and 13.3%, respectively; χ2 = 16.04, degrees of freedom = 2, P < 0.0003). CONCLUSIONS: Simultaneous prescribing of cholinesterase inhibitors, memantine, and anticholinergic medications was significantly less common than in previous studies, with some ethnic variability. The less frequent occurrence of concurrent medications in the Asian population may be because of variations in the rate of indications or in tolerability for anticholinergic medications among the population.

Frontal slow-wave activity as a predictor of negative symptoms, cognition and functional capacity in schizophrenia.

BACKGROUND: Increased temporal and frontal slow-wave delta (1-4 Hz) and theta (4-7 Hz) activities are the most consistent resting-state neural abnormalities reported in schizophrenia. The frontal lobe is associated with negative symptoms and cognitive abilities such as attention, with negative symptoms and impaired attention associated with poor functional capacity. AIMS: To establish whether frontal dysfunction, as indexed by slowing, would be associated with functional impairments. METHOD: Eyes-closed magnetoencephalography data were collected in 41 participants with schizophrenia and 37 healthy controls, and frequency-domain source imaging localised delta and theta activity. RESULTS: Elevated delta and theta activity in right frontal and right temporoparietal regions was observed in the schizophrenia v. CONTROL GROUP: In schizophrenia, right-frontal delta activity was uniquely associated with negative but not positive symptoms. In the full sample, increased right-frontal delta activity predicted poorer attention and functional capacity. CONCLUSIONS: Our findings suggest that treatment-associated decreases in slow-wave activity could be accompanied by improved functional outcome and thus better prognosis.

Frontal and superior temporal auditory processing abnormalities in schizophrenia.

BACKGROUND: Although magnetoencephalography (MEG) studies show superior temporal gyrus (STG) auditory processing abnormalities in schizophrenia at 50 and 100 ms, EEG and corticography studies suggest involvement of additional brain areas (e.g., frontal areas) during this interval. Study goals were to identify 30 to 130 ms auditory encoding processes in schizophrenia (SZ) and healthy controls (HC) and group differences throughout the cortex. METHODS: The standard paired-click task was administered to 19 SZ and 21 HC subjects during MEG recording. Vector-based Spatial-temporal Analysis using L1-minimum-norm (VESTAL) provided 4D maps of activity from 30 to 130 ms. Within-group t-tests compared post-stimulus 50 ms and 100 ms activity to baseline. Between-group t-tests examined 50 and 100 ms group differences. RESULTS: Bilateral 50 and 100 ms STG activity was observed in both groups. HC had stronger bilateral 50 and 100 ms STG activity than SZ. In addition to the STG group difference, non-STG activity was also observed in both groups. For example, whereas HC had stronger left and right inferior frontal gyrus activity than SZ, SZ had stronger right superior frontal gyrus and left supramarginal gyrus activity than HC. CONCLUSIONS: Less STG activity was observed in SZ than HC, indicating encoding problems in SZ. Yet auditory encoding abnormalities are not specific to STG, as group differences were observed in frontal and SMG areas. Thus, present findings indicate that individuals with SZ show abnormalities in multiple nodes of a concurrently activated auditory network.

Toxic effects of psychotropics related to possible p450 enzyme inhibition by kava: report of 2 cases.

Kava is an herbal remedy popular for centuries among native Pacific Islanders for its sedative effects and use in religious ceremonies. Kava gained popularity in Western countries due to its anxiolytic properties; however, very little is known about potential adverse reactions to kava other than reports of hepatotoxicity. Two cases of patients seen on the psychiatric emergency and consult service who developed severe side effects from psychotropic medications in the context of kava use are presented. In both cases, kava use may have affected the metabolism of the psychotropic medications, leading to serious side effects. Growing research indicates that kava most likely alters concentrations of coadministered psychotropics possibly by inhibiting cytochrome P450 enzymes. This case series highlights the need for greater awareness of safety issues among kava users who also take medications that, when combined with kava, can be life-threatening at toxic levels. Pharmacogenomic testing along with further research about kava and its metabolites could help determine a pharmacologic solution for patients who require psychotropic medications but who would like to preserve cultural traditions and religious practices.

Temporal and frontal cortical thickness associations with M100 auditory activity and attention in healthy controls and individuals with schizophrenia.

BACKGROUND: Although gray matter (GM) abnormalities are frequently observed in individuals with schizophrenia (SCZ), the functional consequences of these structural abnormalities are not yet understood. The present study sought to better understand GM abnormalities in SCZ by examining associations between GM and two putative functional SCZ biomarkers: weak 100 ms (M100) auditory responses and impairment on tests of attention. METHODS: Data were available from 103 subjects (healthy controls=52, SCZ=51). GM cortical thickness measures were obtained for superior temporal gyrus (STG) and prefrontal cortex (PFC). Magnetoencephalography (MEG) provided measures of left and right STG M100 source strength. Subjects were administered the Trail Making Test A and the Connors' Continuous Performance Test to assess attention. RESULTS: A strong trend indicated less GM cortical thickness in SCZ than controls in both regions and in both hemispheres (p=0.06). Individuals with SCZ had weaker M100 responses than controls bilaterally, and individuals with SCZ performed more poorly than controls on tests of attention. Across groups, left STG GM was positively associated with left M00 source strength. In SCZ only, less left and right STG and PFC GM predicted poorer performance on tests of attention. After removing variance in attention associated with age, associations between GM and attention remained significant only in left and right STG. CONCLUSIONS: Reduced GM cortical thickness may serve as a common substrate for multiple functional abnormalities in SCZ, with structural-functional abnormalities in STG GM especially prominent. As suggested by others, functional abnormalities in SCZ may be a consequence of elimination of the neuropil (dendritic arbors and associated synaptic infrastructure) between neuron bodies.

Treatment of generalized anxiety disorder: a comprehensive review of the literature for psychopharmacologic alternatives to newer antidepressants and benzodiazepines.

OBJECTIVE: Generalized anxiety disorder (GAD) is common, chronic, and debilitating. Treatment with benzodiazepines and newer antidepressants is often inadequate. This article reviews the effectiveness of alternative and augmenting medications, such as older antidepressants, antipsychotics, anticonvulsants, and ß-blockers. DATA SOURCES: A search using MEDLINE (1980 to week 4 of May 2010) with the key words generalized anxiety disorder or GAD and therapeutics or treatment was conducted. Articles included adult patients with a GAD diagnosis that established chronicity of illness. These included a small number of studies that used DSM-III criteria but added a chronicity of symptoms and included all studies that used DSM-III-R and DSM-IV criteria. Articles that did not include medications or that exclusively focused on newer antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, bupropion, and mirtazapine), buspirone, benzodiazepines, or herbal or investigational medications were excluded. Review articles and non-English-language articles were also excluded. RESULTS: Thirty-six studies were reviewed. All of the references were then analyzed, and key portions were extracted. Many studies were open trials. Double-blind, placebo-controlled studies with imipramine, risperidone, olanzapine, hydroxyzine, ondansetron, tiagabine, valproate, and pregabalin had been conducted. Imipramine, hydroxyzine, valproate, and pregabalin were the most effective, although risperidone, olanzapine, ziprasidone, and aripiprazole may also reduce symptoms. CONCLUSIONS: Several medication strategies can be considered as promising alternatives or augmenting to antidepressant or benzodiazepine therapy in GAD.

Cognitive abilities and 50- and 100-msec paired-click processes in schizophrenia.

OBJECTIVE: Abnormal 50- and 100-msec event-related brain activity derived from paired-click procedures are well established in schizophrenia. There is little agreement on whether group differences in the ratio score, i.e., the ratio of EEG amplitude after the second stimulus (S2) to the amplitude after the first stimulus (S1), reflect an encoding or gating abnormality. In addition, the functional implications remain unclear. In the present study, EEG and magnetoencephalography (MEG) were used to examine paired-click measures and cognitive correlates of paired-click activity. METHOD: EEG and whole-cortex MEG data were acquired during the standard paired-click paradigm in 73 comparison subjects and 79 schizophrenia patients. Paired-click ratio scores were obtained at 50 msec (P50 evoked potential at Cz, M50 at left and right superior temporal gyrus [STG]) and 100 msec (N100 at Cz, M100 at left and right STG). A cognitive battery assessing attention, working memory, and long-delay memory was administered. IQ was also estimated. RESULTS: Groups differed on ratio score and amplitude of S1 response. Ratio scores at 50 msec and 100 msec and S1 amplitude predicted variance in attention (primarily S1 amplitude), working memory, and long-delay memory. The attention findings remained after removal of variance associated with IQ. CONCLUSIONS: Associations between paired-click measures and cognitive performance in patients support 50-msec and 100-msec ratio and amplitude scores as clinically significant biomarkers of schizophrenia. In general, cognitive performance was better predicted by the ability to encode auditory information than the ability to filter redundant information.

Effect of catechol O-methyltransferase val(158)met polymorphism on the p50 gating endophenotype in schizophrenia.

BACKGROUND: Studies have implicated prefrontal dopamine in cortical information filtering. Deficit in stimulus filtering, an endophenotype of schizophrenia, can be demonstrated using the auditory P50 paired-click gating paradigm. The role of prefrontal dopamine on P50 gating was investigated, using catechol-O-methyltransferase (COMT) valine (val)(158)methionine (met) polymorphism as a predictor of prefrontal dopamine activity. METHODS: Twenty-five comparison and 42 schizophrenia subjects underwent P50 gating measurement and COMT genotyping. RESULTS: In the combined sample, COMT polymorphism accounted for a unique 10% of gating variance (p = .02), after variance due to diagnosis, smoking status, and antipsychotic use was removed. Valine homozygous individuals exhibited the greatest gating deficit. CONCLUSIONS: Valine homozygous individuals are more likely to have gating deficits, supporting COMT as a genetic determinant of the P50 endophenotype, as well as a role for prefrontal dopamine in auditory filtering.

Improved test-retest reliability of 50-ms paired-click auditory gating using magnetoencephalography source modeling.

Used to study filtering abnormalities in schizophrenia, the paired-click paradigm suffers from poor test-retest reliability of the gating ratio, calculated from the P50 component of the ERP recorded at Cz approximately 50 ms following each of two stimuli. This study sought to improve reliability by assessing 50-ms gating at primary auditory cortices (PAC), the main generators of the P50 Cz component. MEG source modeling was used, taking advantage of the tangentially oriented PAC sources. Ten healthy subjects underwent three sessions, during which Cz-based and PAC-derived gating was measured. Unlike Cz P50, gating ratios at bilateral PACs achieved an intraclass coefficient of .8 or greater. Variability of gating within the same subject was also significantly smaller for bilateral PACs than for Cz P50. Paired-click gating ratio reliability can be improved by examining the individual PACs rather than composite scalp-recorded activity.