Boris B. Quednow

Impaired prepulse inhibition of acoustic startle in obsessive-compulsive disorder.

BACKGROUND Animal and clinical studies suggest that impaired sensorimotor gating, as assessed with the prepulse inhibition (PPI) paradigm, may result from dysfunctional frontostriatal brain circuits and from neurochemical alterations which are also implied in the pathophysiology of obsessive-compulsive disorder (OCD). However, there is only preliminary evidence about impaired PPI in OCD so far. METHODS Acoustic PPI was measured in 30 OCD patients and 30 matched healthy controls with a paradigm using different prepulse intensities. Psychopathology assessment included ratings for obsessions, compulsions, and depression. RESULTS PPI was reduced in OCD patients, and this deficit was most pronounced for most intense (16 dB(A)) prepulses, where mean PPI was 39.6% in unmedicated patients (n = 4), 45.8% in medicated patients, and 58.9% in controls. No group differences were observed with regard to the habituation of acoustic startle magnitude. Startle measures were generally not associated with clinical measures, although such associations may have been obscured by medication effects. CONCLUSIONS The present study confirms deficient central inhibitory functioning in patients with OCD and supports the model of deficient frontostriatal circuits in OCD. The relationship of PPI deficits to pharmacological and behavioral treatment and to possible subtypes of OCD merits further study.

Elevated impulsivity and impaired decision-making cognition in heavy users of MDMA (“Ecstasy”)

RationaleIn animal studies, the common club drug 3,4-methylendioxymethamphetamine (MDMA, “Ecstasy”) consistently caused a prolonged loss of presynaptic serotonergic neurons, and evidence suggests that MDMA consumption may also affect the human serotonergic system. Serotonin (5-HT) has been implicated in the regulation of impulsivity and such executive functions as decision-making cognition. In fact, MDMA users have shown elevated impulsivity in two studies, but little is known about decision making in drug-free MDMA consumers.ObjectiveThe aim of this study was to examine the cognitive neurotoxicity of MDMA with regard to behavioral impulsivity and decision-making cognition.MethodsNineteen male, abstinent, heavy MDMA users; 19 male, abstinent cannabis users; and 19 male, drug-naïve controls were examined with the Matching Familiar Figures Test (MFFT) as well as with a Go/No-Go Task (GNG) for impulsivity and with a Gambling Task (GT) for executive functioning.ResultsMDMA users showed significantly elevated impulsivity in the MFFT Impulsivity score (I-score), but not in commission errors of the GNG, compared with controls. Cannabis users did not yield altered impulsivity compared with controls. In the GT, MDMA users performed significantly worse than cannabis consumers and controls, whereas cannabis users exhibited the same decision-making capacity as controls. In addition, the I-score as well as the decision-making performance was correlated with measures of MDMA intake. The I-score and the decision-making performance were also correlated.ConclusionThese results suggest that heavy use of MDMA may elevate behavioral impulsivity and impair decision-making cognition possibly mediated by a selective impairment of the 5-HT system.

Impaired Sensorimotor Gating of the Acoustic Startle Response in the Prodrome of Schizophrenia

BACKGROUND Schizophrenia patients exhibit impairment in prepulse inhibition (PPI) of the acoustic startle response (ASR), which is commonly interpreted as a sensorimotor gating deficit. To date, it is unclear when these gating deficits arise. Results of animal studies and some human data suggest that PPI deficits are in part genetically determined, such that gating deficits could be present before the onset of a full-blown psychosis. To test this assumption, we investigated PPI of ASR in individuals with prodromal symptoms of schizophrenia and patients with first-episode schizophrenia. METHODS Startle reactivity, habituation, and PPI of ASR, as well as a neuropsychological test battery, were assessed in 54 subjects with prodromal symptoms of schizophrenia (35 early and 19 late prodromal subjects), 31 first-episode schizophrenia patients (14 unmedicated, 17 medicated), and 28 healthy control subjects. Patients were also examined with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale. RESULTS Prodromal subjects and unmedicated patients with first-episode schizophrenia showed significant PPI deficits, whereas schizophrenia patients treated with risperidone had almost normal PPI. Startle reactivity decreased with greater severity of symptoms (control subjects, early prodromal group > late prodromal group > unmedicated first-episode patients) but was almost normal in the medicated patients. With respect to habituation, prodromal subjects and schizophrenia patients did not differ from healthy control subjects. CONCLUSIONS PPI disruption is already present in a prodromal state of schizophrenia, but startle reactivity deficits seem to emerge with the onset of acute psychosis.

Sensorimotor Gating and Habituation of the Startle Response in Schizophrenic Patients Randomly Treated With Amisulpride or Olanzapine

BACKGROUND Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. METHODS The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. RESULTS Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. CONCLUSIONS Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

Executive performance of depressed suicide attempters: the role of suicidal ideation

ObjectiveSuicidal ideation has been related to cognitive rigidity whereas suicidal behaviour itself was associated with specific executive deficits. Yet it remains unclear if a distinct cognitive suicidal phenotype does exist. The aim of the present study was to further investigate the role of suicidal thinking for the neuropsychological performance in depressive suicide attempters.MethodDepressive inpatients after a recent suicide attempt, who either had present suicidal ideation (n = 14) or not (n = 15) and healthy controls (n = 29) were recruited. The groups were assessed by means of executive tasks designed to capture impulsive decision-making, and with verbal memory and attention tests. Self-rating measures of impulsivity and aggression were further applied.ResultsOnly patients with current suicidal ideation showed executive dysfunctions with impaired decision-making being the most salient. Verbal memory and attention were reasonably intact in all patients. All patients reported increased aggression.ConclusionSuicidal ideation is clearly associated with impaired cognitive performance. Our results suggest that executive deficits seen in depressive suicide attempters have a state-dependent component.

Cognitive dysfunctions in recreational and dependent cocaine users: role of attention-deficit hyperactivity disorder, craving and early age at onset

BACKGROUND Dependent cocaine users consistently display cognitive deficits but cognitive performance of recreational cocaine users has rarely been investigated. AIMS To examine whether cognitive performance is impaired in relatively pure recreational and dependent cocaine users. METHOD The cognitive performance of recreational (n = 68) and dependent cocaine users (n = 30) was compared with the performance of stimulant-naive controls (n = 68) employing an extensive neuropsychological test battery. Moreover, the impact of attention-deficit hyperactivity disorder (ADHD) symptoms, craving and early age at onset was analysed. RESULTS Dependent cocaine users display broad cognitive impairments in the domains of attention, working memory, declarative memory and executive functions. The performance of recreational cocaine users in all four domains was intermediate between that of controls and dependent users and they displayed significant deficits foremost in the domains of attention and working memory. In addition, ADHD symptoms, craving and age at onset were important modulators of cognitive function in cocaine users. CONCLUSIONS Cognitive deficits occur at a recreational and non-dependent level of cocaine use. Cocaine use and ADHD seem to have mutually aggravating effects on cognitive impairment.

On the Influence of Baseline Startle Reactivity on the Indexation of Prepulse Inhibition

Prepulse inhibition (PPI) of the startle reflex refers to the reduction of the reflexive startle response to an intense pulse stimulus when its presentation is shortly preceded by a weak prepulse stimulus. PPI is considered as a cross-species translational model of sensorimotor gating, and deficient PPI has been reported in a number of neuropsychiatric disorders. Although a part of the literature is based on the assumption that PPI is independent of the baseline startle reaction, there is accumulating evidence (Csomor et al., 2006; Sandner & Canal, 2007; Yee, Chang, Pietropaolo, & Feldon, 2005) that argues against such an independency. The authors systematically investigated whether PPI indexed as percentage or difference score is dependent on the magnitude of baseline startle reactivity in healthy human volunteers and in C57BL/6 mice. The results revealed that both indexations of PPI were affected by the magnitude of the baseline startle. The authors highlight the pitfalls of different methods to index PPI, especially when startle reactivity differs considerably between groups under comparison, and offer practical recommendations to satisfactorily deal with such baseline differences.

Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants

Major depression (MD) is underdiagnosed and undertreated in patients with temporal lobe epilepsy (TLE). Side effects of some antidepressants, like increased risk of seizures and drug-drug interactions with anticonvulsants, contribute to undertreatment of MD in patients with TLE. We analyzed post hoc the data from 2 years of treatment of inpatients with MD and TLE. Seventy-five patients received standard treatment with citalopram, mirtazapine, or reboxetine, respectively, at recommended dosage. Examinations were done with the Hamilton Rating Scale for Depression at admission and after 4 and 20-30 weeks. Plasma levels of anticonvulsants were examined at admission and discharge. Seizures were documented. The antidepressive treatment was efficacious in all antidepressant groups. No case of serious adverse event or drug interaction occurred. There was no increase in frequency or severity of seizures. At endpoint the dropout rate for mirtazapine was significantly higher than that for reboxetine or citalopram. Reboxetine showed a trend to be more efficacious than citalopram but not mirtazapine at Week 4.

Memory deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction

Chronic administration of the common club drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and non-human primates, and evidence suggests that recreational MDMA consumption may also affect the human serotonergic system. Moreover, it was consistently shown that abstinent MDMA users have memory de.cits. Recently, it was supposed that these de.cits are an expression of a temporal or rather hippocampal dysfunction caused by the serotonergic neurotoxicity of MDMA. The aim of this study is to examine the memory de.cits of MDMA users neuropsychologically in order to evaluate the role of different brain regions. Nineteen male abstinent MDMA users, 19 male abstinent cannabis users and 19 male drug-naive control subjects were examined with a German version of the Rey Auditory Verbal Learning Test (RAVLT). MDMA users showed widespread and marked verbal memory de.cits, compared to drug-naive controls as well as compared to cannabis users, whereas cannabis users did not differ from control subjects in their memory performance. MDMA users revealed impairments in learning, consolidation, recall and recognition. In addition, they also showed a worse recall consistency and strong retroactive interference whereby both measures were previously associated with frontal lobe function. There was a signi.cant correlation between memory performance and the amount of MDMA taken. These results suggest that the memory de.cits of MDMA users are not only the result of a temporal or hippocampal dysfunction, but also of a dysfunction of regions within the frontal cortex.

Prepulse inhibition and habituation of acoustic startle response in male MDMA ('ecstasy') users, cannabis users, and healthy controls.

Chronic administration of 3,4-methylenedioxymethamphetamine (MDMA) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and nonhuman primates. Despite the broad database concerning the selective serotonergic neurotoxicity of recreational MDMA consumption by humans, controversy still exists with respect to the question of whether the well-known functional consequences of these neurotoxic effects, such as memory impairment, were caused by chronic 5-HT deficiency. Habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) can be used as a marker of central serotonergic functioning in rodents and humans. Thus, we investigated the functional status of the central serotonergic system in chronic but abstinent MDMA users by measuring PPI and habituation of ASR. PPI and habituation of ASR were measured in three groups. The first group (MDMA group) included 20 male drug-free chronic users of MDMA; the second group (cannabis group) consisted of 20 male drug-free chronic users of cannabis; and the third group (healthy controls) comprised 20 male participants with no history of illicit drug use. Analysis revealed significantly increased PPI of MDMA users compared to those of cannabis users and healthy controls. Cannabis users and healthy controls showed comparable patterns of PPI. There were no differences in habituation among the three groups. These results suggest that the functional consequences of chronic MDMA use may be explained by 5-HT receptor changes rather than by a chronic 5-HT deficiency condition. Use of cannabis does not lead to alterations of amplitude, habituation, or PPI of ASR.