Family history of alcohol dependence and antidepressant response to an N‐methyl‐D‐aspartate antagonist in bipolar depression

Luckenbaugh DA, Ibrahim L, Brutsche N, Franco‐Chaves J, Mathews D, Marquardt CA, Cassarly C, Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N‐methyl‐d ‐aspartate antagonist in bipolar depression. Bipolar Disord 2012: 14: 880–887. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. Objectives: Both ketamine and ethanol are N‐methyl‐d ‐aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine’s antidepressant and perceptual effects in individuals with bipolar depression. Methods: A post hoc analysis was conducted on 33 subjects with DSM–IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double‐blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post‐infusion. The primary outcome measure was Montgomery‐Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first‐degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. Results: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. Conclusions: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic‐based therapies for depression.     

Ketamine, Sleep, and Depression: Current Status and New Questions

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described rapid antidepressant effects in clinical studies of individuals with treatment-resistant major depressive disorder (MDD). Preclinical studies investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF) and on sleep slow wave activity (SWA) support its use as a prototype for investigating the neuroplastic mechanisms presumably involved in the mechanism of rapidly acting antidepressants. This review discusses human EEG slow wave sleep parameters and plasma BDNF as central and peripheral surrogate markers of plasticity, and their use in assessing ketamine’s effects. Acutely, ketamine elevates BDNF levels, as well as early night SWA and high-amplitude slow waves; each of these measures correlates with change in mood in depressed patients who respond to ketamine. The slow wave effects are limited to the first night post-infusion, suggesting that their increase is part of an early cascade of events triggering improved mood. Increased total sleep and decreased waking occur during the first and second night post infusion, suggesting that these measures are associated with the enduring treatment response observed with ketamine.     

Is inadequate family history a barrier to diagnosis in CADASIL?

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has typical clinical features that include stroke, migraine, mood disturbances and cognitive decline. However, misdiagnosis is common. We hypothesized that family history is poorly elicited in individuals presenting with features of CADASIL and that enquiry into family history of all four cardinal manifestations of CADASIL is superior to elicitation of family history of premature stroke alone in raising the diagnostic possibility of CADASIL. MATERIALS AND METHODS: Retrospective review of family histories at presentation in 40 individuals with confirmed CADASIL was performed through structured interview in a Neurovascular Genetics clinic (182 first-degree and 242 second-degree relatives identified). Family history obtained from structured interview was compared to family history initially documented at presentation. RESULTS: At initial presentation, 30% of individuals were inaccurately documented to have no family history of significant neurological illness. Thirty-five per cent of patients had an initial alternative diagnosis. Initial inaccurate documentation of negative family history was more frequent in individuals with an initial alternative diagnosis. After structured interviews, 34% of 182 first-degree and 35% of 242 second-degree relatives of CADASIL patients had history of stroke (16% of first-degree relatives had stroke before the age of 50 years). Forty-three per cent of first-degree and 28% of second-degree relatives had migraine, mood disturbance or cognitive decline. CONCLUSIONS: A false-negative family history was commonly documented in individuals presenting with features of CADASIL and was associated with initial misdiagnosis. Restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees.     

Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists

BACKGROUND: The cognitive, behavioral, and mood effects of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine, have been used to study the effects of NMDA receptor dysfunction. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia. Preclinical studies indicate that some ketamine effects may be mediated through increased glutamate release. In this study, we tested the hypothesis that lamotrigine, a drug reported to inhibit glutamate release, will reduce the neuropsychiatric effects of ketamine in humans. METHOD: Healthy subjects (n = 16) completed 4 test days involving the administration of lamotrigine, 300 mg by mouth, or placebo 2 hours prior to administration of ketamine (0.26 mg/kg by intravenous bolus and 0.65 mg/kg per hour by intravenous infusion) or placebo in a randomized order under double-blind conditions. Behavioral and cognitive assessments were performed at baseline and after administration of the medications. RESULTS: Lamotrigine significantly decreased ketamine-induced perceptual abnormalities as assessed by the Clinician-Administered Dissociative States Scale (P<.001); positive symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P<.001); negative symptoms as assessed by the Brief Psychiatric Rating Scale negative symptoms subscale (P<.05); and learning and memory impairment as assessed by the Hopkins Verbal Learning Test (P<.05). However, lamotrigine increased the immediate mood-elevating effects of ketamine (P<.05). CONCLUSIONS: Glutamate release-inhibiting drugs may reduce the hyperglutamatergic consequences of NMDA receptor dysfunction implicated in the pathophysiologic processes of neuropsychiatric illnesses such as schizophrenia. Further study is needed.     

N-methyl-D-aspartate receptor in working memory impairments in schizophrenia: event-related potential study of late stage of working memory process

Working memory (WM) deficit in schizophrenic patients has been well established. Still, underlying biological substrate of the impairment is not clear. Among neurotransmitter hypotheses of schizophrenia, N-methyl-D-aspartate (NMDA) receptor model is mostly supported, considering that NMDA receptor antagonist can elicit both psychosis and cognitive impairment observed in schizophrenic patients. In current study, to test the neuropsychological and the electrophysiological effects of NMDA receptor in WM, event-related potentials (ERPs) of Sternberg's short-term memory scanning task (SMST) were analyzed in 10 healthy subjects under intravenous administration of a subanesthetic dose of ketamine (0.65 mg/kg/h) or placebo (normal saline). Late positive component (LPC) of ERP was hypothesized to reflect later stage of WM. Brief Psychiatric Rating Scale score was significantly increased (t=-5.75, df=9, P<.001) and correct response rate was significantly decreased (t=2.21, df=9, P=.054) after ketamine administration. Neither reaction time nor LPC latency, which reflect memory scanning time, was changed. Amplitude of LPC was significantly reduced after ketamine administration (z=-2.31, number of observations=120, P=.021). In conclusion, NMDA receptor antagonist administration elicited WM deficit both in behavioral and electrophysiological level. Electrophysiological component reflecting later stage of WM was impaired by NMDA antagonist.     

Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia.

OBJECTIVE: This study sought to determine whether thought disorder induced in healthy volunteers by the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine resembles the thought disorder found in patients with schizophrenia. METHOD: The Scale for the Assessment of Thought, Language, and Communication was used to assess thought disorder in healthy volunteers (N = 10) who received subanesthetic doses of ketamine and in a group of clinically stable inpatients with schizophrenia (N = 15) who did not receive ketamine. RESULTS: Mean scores on the Scale for the Assessment of Thought, Language, and Communication for patients with schizophrenia and healthy volunteers receiving ketamine did not differ significantly. Moreover, three of the four highest rated test items in both groups were the same. CONCLUSIONS: These data suggest that ketamine-induced thought disorder in healthy volunteers is not dissimilar to the thought disorder in patients with schizophrenia and provide support for the involvement of the NMDA receptor in a cardinal symptom of schizophrenia.     

Ketamine augmentation rapidly improves depression scores in inpatients with treatment-resistant bipolar depression

Objective: To study the clinical effect of a single ketamine infusion, 0.5?mg/kg body weight, in bipolar depressive patients receiving mood-stabilising drugs, not improving on antidepressants. Previously, in such patients, we had found a correlation between clinical efficacy, serum brain-derived neurotrophic factor and vitamin B12 levels and a rapid improvement in neurocognitive performance.

Methods: The study included 53 patients (13 men, 40 women), aged 22–81 years, receiving ≥1 mood-stabilising medications of the first and/or second generation. Pre-infusion depression intensity on the Hamilton Depression Rating Scale (HDRS) was 23.4?±?4.6 points and the assumed criterion for response was a reduction of ≥50% in the HDRS score after 7 days.

Results: Twenty-seven subjects (51%) met a criterion for response, more frequently males (77%) than females (43%). Responders did not differ from non-responders as to age, illness onset, duration of depressive episode, type of bipolar illness, family history of psychiatric illness, personal/family history of alcoholism or using lithium, quetiapine or a combination of these mood stabilisers.

Conclusions: The results confirm a rapid antidepressant effect of ketamine infusion in a considerable proportion of those patients with bipolar depression receiving mood-stabilising drugs. Apart from male gender, no other clinical factors were predictors of response.     

Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism.

OBJECTIVE: A deficit in serotonergic neurotransmission has been linked to impulsive behavior, as well as to disorders characterized by disinhibition. The present study tested the hypothesis that young men at high risk for alcoholism demonstrate greater behavioral disinhibition after acute dietary depletion of tryptophan, the amino acid precursor of serotonin. METHOD: A double-blind, placebo-comparison, between-subjects study design was used. Nonalcoholic young men with a multigenerational paternal family history of alcoholism (N = 13) or with no family history of alcoholism (N = 15) in two previous generations were administered mixtures of tryptophan-deficient amino acid to achieve plasma tryptophan depletion. Comparison subjects with a multigenerational paternal family history of alcoholism (N = 1) and comparison subjects with no family history of alcoholism (N = 18) were given a balanced mixture. Five hours after this, all were tested on a modified Taylor task and a go/ no-go task measuring aggressive response and disinhibition, respectively. RESULTS: Plasma tryptophan levels were reduced by 89% in both groups. Tryptophan depletion had no effect on aggressive response. In contrast, tryptophan-depleted individuals with a family history of alcoholism made more commission errors (responses to stimuli associated with punishment or loss of reward) than did tryptophan-depleted individuals with no family history of alcoholism and those receiving the balanced (comparison) mixture of amino acid in either group. CONCLUSIONS: Low serotonin levels may be implicated in the high disinhibition or impulsivity observed in some individuals with a genetic vulnerability to alcohol abuse or dependence.     

Glutamate modulators as novel interventions for mood disorders

Recent evidence suggests that critical molecules in neurotrophic signaling cascades are long-term targets for currently available monoaminergic antidepressants. As chronic and severe mood disorders are characterized by impairments in neuronal resilience, pharmacological strategies that subserve a neuroprotective function might alter disorder pathophysiology and modify disease progression. Several promising approaches involve modulation of the glutamate neurotransmitter system, via post-synaptic receptor blockade or potentiation and presynaptic vesicular release inhibition. A focused review of the extant scientific literature was conducted, with a discussion of 3 compounds or classes of drugs currently undergoing clinical investigation: ketamine, riluzole, and AMPA receptor potentiators. Recent investigations in mood disordered patients suggest that the NMDA receptor antagonist ketamine might demonstrate rapid antidepressant properties. Riluzole has been shown to reverse glutamate-mediated impairments in neuronal plasticity and to stimulate the synthesis of brain derived neurotrophic factor. Open-label trials in treatment-resistant depression have yielded promising results. Likewise, AMPA receptor potentiators favorably impact neurotrophic factors as well as enhance cognition. CONCLUSIONS: Pharmacological approaches that modulate components of the glutamate system offer novel targets for severe, recurrent mood disorders. Controlled studies are necessary.     

Subanaesthetic Ketamine Treatment Alters Prefrontal Cortex Connectivity With Thalamus and Ascending Subcortical Systems

Background: Acute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the functional deficits associated with this disorder and shows reduced activity (hypofrontality) in schizophrenia patients. Chronic NMDA antagonist treatment in rodents can also induce hypofrontality, although paradoxically acute NMDA receptor antagonist administration induces metabolic hyperfrontality. Methods: In this study, we use 2-deoxyglucose imaging data in mice to characterize acute ketamine-induced alterations in regional functional connectivity, a deeper analysis of the consequences of acute NMDA receptor hypofunction. Results: We show that acute ketamine treatment increases PFC metabolic activity while reducing metabolic activity in the dorsal reticular thalamic nucleus (dRT). This is associated with abnormal functional connectivity between the PFC and multiple thalamic nuclei, including the dRT, mediodorsal (MDthal), and anteroventral (AVthal) thalamus. In addition, we show that acute NMDA receptor blockade alters the functional connectivity of the serotonergic (dorsal raphe [DR]), noradrenergic (locus coeruleus [LC]), and cholinergic (vertical limb of the diagonal band of broca [VDB]) systems. Conclusions: Together with other emerging data, these findings suggest that the reticular nucleus of the thalamus, along with the diffusely projecting subcortical aminergic/cholinergic systems, represent a primary site of action for ketamine in reproducing the diverse symptoms of schizophrenia. Our results also demonstrate the added scientific insight gained by characterizing the functional connectivity of discrete brain regions from brain imaging data gained in a preclinical context.     

Altered prefrontal dopaminergic function in chronic recreational ketamine users

OBJECTIVE: Ketamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D1 receptor availability was assessed by using positron emission tomography and the selective D1 receptor radioligand [11C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects. METHOD: History of ketamine abuse was confirmed in subjects by hair analysis. [11C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function. RESULTS: Dorsolateral prefrontal cortex D1 receptor availability was significantly up-regulated in chronic ketamine users ([11C]NNC 112 binding potential: mean=1.68 ml/g, SD=0.40) relative to comparison subjects (mean=1.35 ml/g, SD=0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [11C]NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week. CONCLUSIONS: Chronic ketamine users exhibited a regionally selective up-regulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.     

大鼠CVLM中NMDA和非NMDA受体在介导动脉压力感受器反射中的作用

在氨基甲酸乙酯麻醉、制动的大鼠 ,研究尾端延髓腹外侧区 (CVLM)中 NMDA和非 NMDA受体在介导动脉压力感受器反射 (ABR)中的作用。双侧 CVLM微量注射选择性 NMDA受体拮抗剂氯胺酮 (50mmol/L ,1 0 0 nl)或非 NMDA受体拮抗剂 kynurenic acid(KYA,50 mmol/L ,1 0 0 nl)后平均动脉压 (MAP)和心率 (HR)均明显升高 (P<0 .0 5) ,同时观察到 CVLM微量注射氯胺酮或 KYA后电刺激主动脉神经(AN)导致的血压下降比对照有明显的减少 ,双侧 CVLM微量注射氯胺酮和 KYA的混合物 (均为 50mmol/L,50 nl)后能完全阻断电刺激 AN后导致的降压反应。本研究结果提示 CVLM中 NMDA和非 NM-DA受体在紧张性维持交感神经的兴奋活动和介导 ABR中起十分重要的作用     

A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation

PURPOSE: New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs. METHODS: Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex. RESULTS: Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE. DISCUSSION: This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.     

Antidepressant effects of ketamine in depressed patients.

BACKGROUND: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. METHODS: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. RESULTS: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). CONCLUSIONS: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.     

Effect of ketamine on the neuromagnetic mismatch field in healthy humans

Mismatch negativity (MMN) is a component of the auditory evoked event-related potentials (ERP) that assesses automatic sound change detection and is disturbed in schizophrenic patients. Animal experimental evidence has linked the generation of MMN to the N-methyl-D-aspartate (NMDA) receptor. We investigated the neuromagnetic mismatch field (MMF) in healthy volunteers before and after intravenous application of a subanesthetic dose of the NMDA receptor antagonist ketamine (0.3 mg/kg). Ketamine had a significant influence on latency and dipole moment of the MMF, whereas the N100m latency of the standard tone was not prolonged and its dipole moment remained stable. Our results suggest that ketamine interferes with aspects of preattentive information processing and is in line with the view that disturbed NMDA receptor function may mediate the deficient auditory mismatch response in patients with schizophrenia.     

Ketamine for Treatment of Suicidal Ideation and Reduction of Risk for Suicidal Behavior

Ketamine, an NMDA receptor antagonist with efficacy as a rapid anti-depressant, has early evidence for action to reduce suicidal ideation. This review will explore several important questions that arise from these studies. First, how do we measure reductions in suicidal ideation that occur over minutes to hours? Second, are the reductions in suicidal ideation after ketamine treatment solely a result of its rapid anti-depressant effect? Third, is ketamine only effective in reducing suicidal ideation in patients with mood disorders? Fourth, could ketamine’s action lead us to a greater understanding of the neurobiology of suicidal processes? Last, do the reductions in depression and suicidal ideation after ketamine treatment translate into decreased risk for suicidal behavior? Our review concludes that ketamine treatment can be seen as a double-edged sword, clinically to help provide treatment for acutely suicidal patients and experimentally to explore the neurobiological nature of suicidal ideation and suicidal behavior.     

Caffeine dependence in combination with a family history of alcoholism as a predictor of continued use of caffeine during pregnancy

OBJECTIVE: The purpose of the study was to examine whether caffeine dependence and a family history of alcoholism are associated with continued use of caffeine during pregnancy. METHOD: Forty-four women seeking obstetrical care in an office-based practice completed questionnaires and provided saliva samples at three prenatal visits occurring 2-3, 3-4, and 7 months postconception. On visit 1, the patients received the physician's instructions to stop using caffeine. Structured interviews were used to assign a diagnosis of caffeine dependence (lifetime) and to identify family history of alcoholism. Outcome measures included self-reported levels of caffeine use and saliva caffeine levels at the three prenatal visits. RESULTS: Although most women eliminated or substantially reduced their caffeine consumption between pregnancy awareness and prenatal visit 1, those with a lifetime diagnosis of caffeine dependence and a family history of alcoholism had higher levels of caffeine use and lower rates of abstinence throughout pregnancy. Saliva caffeine levels confirmed these effects. Withdrawal symptoms, functional impairment, and craving were cited as reasons they failed to eliminate or cut back on caffeine use. Fifty percent of the women with both a lifetime diagnosis of caffeine dependence and a family history of alcoholism continued to use caffeine in amounts (>300 mg/day) greater than those considered safe during pregnancy, compared to none of the women without caffeine dependence and a family history of alcoholism. Women with a lifetime diagnosis of caffeine dependence and a family history of alcoholism also reported higher rates of past cigarette smoking and problematic alcohol use. CONCLUSIONS: Caffeine-dependent women with a family history of alcoholism were not able to follow their physician's advice to reduce or eliminate caffeine consumption during pregnancy, despite their wanting to do so. This subgroup may require more intensive intervention to ensure caffeine abstinence and may be at greater risk for abuse of or dependence on other drugs.     

A systematic review of therapeutic ketamine use in children and adolescents with treatment-resistant mood disorders

Suicide is the second leading cause of death in the United States among individuals aged 10–24, and severe youth depression is often refractory to the current standards of care. Many studies have demonstrated the efficacy of ketamine in reducing depressive symptoms in adults with treatment-resistant mood disorders, though few studies utilizing ketamine in youth populations exist. This systematic review examines the current state of evidence for ketamine use in children with treatment-resistant mood disorders. We conducted a search utilizing two electronic databases for English-language studies investigating the therapeutic effects and side effect profile of ketamine in youth ≤ 19 years of age with a diagnosis of a treatment-resistant mood disorder. Analysis included subjects with treatment-resistant depression with and without psychotic features and with bipolar disorder. Primary outcome measures included the following scales: Montgomery–Asberg Depression Rating Scale, Children’s Depression Rating Scale, Children’s Depression Rating Scale Revised, Child Bipolar Questionnaire, Overt Aggression Scale, Yale–Brown Obsessive–Compulsive Scale, and Scale for Suicidal Ideation. Four published studies were identified that investigated therapeutic ketamine use in youth for the primary purpose of treating a treatment-resistant psychiatric disorder. Three additional studies that did not meet eligibility criteria were identified and discussed. Ketamine was shown in youth to generally improve depressive symptoms, decrease acute suicidality, and reduce mood lability, though a number of subjects remained resistant to its treatment. These findings substantiate the need for further longitudinal studies investigating ketamine’s long-term safety, its efficacy, and abuse potential in the youth.

     

Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers.

BACKGROUND: Previous studies indicate that mismatch negativity (MMN)-a preattentive auditory event-related potential (ERP)-depends on NMDA receptor (NMDAR) functioning. To explore if the strength of MMN generation reflects the functional condition of the NMDAR system in healthy volunteers, we analyzed correlations between MMN recorded before drug administration and subsequent responses to the NMDAR antagonist ketamine or the 5-HT2a agonist psilocybin. METHODS: In two separate studies, MMN was recorded to both frequency and duration deviants prior to administration of ketamine or psilocybin. Behavioral and subjective effects of ketamine and psilocybin were assessed with the Brief Psychiatric Rating Scale and the OAV Scale-a rating scale developed to measure altered states of consciousness. Correlations between ERP amplitudes (MMN, N1, and P2) and drug-induced effects were calculated in each study group and compared between them. RESULTS: Smaller MMN to both pitch and duration deviants was significantly correlated to stronger effects during ketamine, but not psilocybin administration. No significant correlations were observed for N1 and P2. CONCLUSIONS: Smaller MMN indicates a NMDAR system that is more vulnerable to disruption by the NMDAR antagonist ketamine. MMN generation appears to index the functional state of NMDAR-mediated neurotransmission even in subjects who do not demonstrate any psychopathology.     

Clinical features of depressed patients with or without a family history of alcoholism

OBJECTIVE: To compare clinical features of depressed subjects without alcoholism but with a family history of alcoholism to a depressed group without alcoholism and without a family history of alcoholism. METHOD: Clinical and demographic data of 209 depressed subjects without a history of alcoholism in first-degree relatives and 73 depressed individuals with a history of alcoholism in first-degree relatives were compared. Subjects with a personal history of alcoholism were excluded. RESULTS: Depressed subjects with a family history of alcoholism have a significantly higher prevalence of reported childhood physical and sexual abuse and post-traumatic stress disorder (PTSD), make more suicide attempts, and have greater intent to die at the time of their most lethal suicide attempt, compared to depressed subjects without a family history of alcoholism. CONCLUSION: Depressed patients with a family history of alcoholism are at greater risk for suicidal behavior and PTSD and may require more careful management.