clozapine and Attention-Deficit-Disorder-with-Hyperactivity

Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.. This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha(7) nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha(7) nicotinic receptor agonists may ameliorate some of these deficits.. Impaired auditory sensory gating has been linked to the alpha(7) nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha(7) nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha(7) nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures.. Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

Topics: Acoustic Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzylidene Compounds; Chromosomes, Human, Pair 15; Clozapine; Evoked Potentials, Auditory; Humans; Neural Inhibition; Nicotinic Agonists; Polymorphism, Single Nucleotide; Pyridines; Receptors, Nicotinic; Schizophrenia; Sensation Disorders

Among patients with treatment-resistant schizophrenia (TRS), some exhibited further clozapine resistance (CR). This study aimed to investigate whether greater severity of treatment resistance in schizophrenia is associated with greater impairments in sustained attention.. Patients with a DSM-IV-defined schizophrenia were recruited from a psychiatric center in northern Taiwan (April 2010 to October 2010). Both TRS and CR were determined retrospectively from participants' medical records following the consensus guidelines. The patients were divided into three groups: 102 non-TRS, 48 TRS without CR, and 54 TRS with CR. They underwent both undegraded and degraded Continuous Performance Tests (CPT), and their performance scores (d') were standardized against a community sample to derive age-, sex-, and education-adjusted z scores.. The TRS with CR group had significantly lower adjusted z scores of d' on both undegraded and degraded CPTs than the other two groups. Meanwhile, the differences between the TRS without CR group and the non-TRS group were not significant. Multivariable linear regression analyses with adjustment for covariates revealed a trend of gradient impairments on the degraded CPT from non-TRS to TRS without CR and to TRS with CR. The proportions of attentional deficits (an adjusted z score of ≤ - 2.5) on the degraded CPT also exhibited a significant trend, from 36.3% in the non-TRS group to 62.5% in the TRS without CR group and to 83.3% in the TRS with CR group.. Greater severity of treatment resistance in schizophrenia was associated with greater impairments in sustained attention, indicating some common vulnerability.

Topics: Adult; Antipsychotic Agents; Attention; Attention Deficit Disorder with Hyperactivity; Clozapine; Drug Resistance; Female; Humans; Linear Models; Male; Middle Aged; Neuropsychological Tests; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Taiwan

Attentional deficits are prominent in the cognitive profile of patients with schizophrenia. However, it remains unclear whether treatment with clozapine, an atypical antipsychotic and first-line intervention used to reduce positive and negative symptoms of psychosis, improves the attentional functions. We used the revised attention network test to measure alerting, orienting, and executive control of attention both pre- and post-treatment with clozapine in patients with schizophrenia (n=32) and compared performance to healthy controls (n=32). Results revealed that there were deficits in all three attentional functions pre-treatment, and while clozapine improved the orienting function in patients with schizophrenia, there was no evidence for improvement in the alerting and executive control of attention. The enhancement of the orienting function by clozapine may increase the ability of patients with schizophrenia to orient towards objects and thoughts of interest.

Topics: Adult; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Clozapine; Executive Function; Female; Humans; Male; Neuropsychological Tests; Orientation; Psychiatric Status Rating Scales; Schizophrenia; Statistics as Topic; Young Adult

A functional analysis examined the relation between consequences that maintained episodic problem behavior (aggression, property destruction, and elopement) in the presence and absence of manic behaviors (MB). Results suggested that the presence of MB was correlated with the sensitivity of problem behavior to attention as a reinforcer during a functional analysis and that problem behaviors were maintained by attention. Noncontingent reinforcement was subsequently implemented and demonstrated to be effective in reducing problem behavior during the presence of manic behaviors.

Topics: Antimanic Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Behavioral Symptoms; Clozapine; Diagnosis, Dual (Psychiatry); Female; Humans; Mental Disorders; Middle Aged; Psychiatric Status Rating Scales; Valproic Acid

The aggregation of psychiatric disorders within families is well-known. The relative role of biological, psychogenic and socialization-related factors varies with the individual case. Another well-known fact is that parents play a very important role in influencing whether their child gets the right treatment when it is necessary. In this paper we highlight the complex links between childhood and adulthood through the presentation of three psychiatric cases. The first story starts with a lactation psychosis of a mother and ends when the daughter who became psychotic at the age of 15 enters adulthood. During these 18 years several psychiatrically relevant episodes happened in the family. During our care, step by step, in relation to emerging psychological problems, the family revealed more and more secrets, explaining past events, and offering a possibility for psychoeducation and psychotherapy. Knowledge concerning the life and psychiatric history of parents, in spite of the fears of the family, largely contributed to evaluating the symptoms of the daughter, reaching a diagnosis, initiating and maintaining therapy and achieving the present balanced state. The next two cases present the stories of two boys with Attention-Deficit/Hyperactivity Disorder (ADHD). One of the children was 6 years old when the family sought professional help, and now he is 11, the other child was 8 years old when the parents sought help and he is 15 now. The two families reacted differently to the offered treatment, but in both cases the family stayed continuously in touch with their child psychiatrists. With these two different stories on ADHD we would like to present several issues and successes which may surface during the long-term treatment of ADHD.

Topics: Adolescent; Adolescent Behavior; Adult; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Child; Clozapine; Epilepsy, Generalized; Family; Fathers; Female; Humans; Hungary; Low Back Pain; Male; Mothers; Pregnancy; Pregnancy Complications; Psychotic Disorders

Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.

Topics: Animals; Antipsychotic Agents; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Motor Activity; Psychomotor Agitation; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Behavior; Social Behavior Disorders

The spontaneously hypertensive rat (SHR) is the most widely used animal model of ADHD. SHR has been found to have increased glutamate-stimulated noradrenaline release from varicosities in several brain areas. Besides its effects on dopamine D4 receptors, clozapine, an atypical antipsychotic with antagonistic effects on α(1)-adrenoceptors, may reduce activation of α(1)-adrenoceptors in SHR and thereby attenuate their hyperactivity. The aims of the study were to determine the effect of clozapine (post-natal day (P) 21-P35, 10 mg/kg/day) on SHR and Wistar-Kyoto (WKY), SHR's normotensive control, and a standard laboratory strain, Sprague Dawley (SD). Rat behaviour was assessed in the open field (P32), novel object (P33) and elevated plus maze (P34) tests that measured locomotor and anxiety-related behaviour. An in vitro superfusion technique was used to measure [(3)H]noradrenaline release in prefrontal cortex (PFC) and hippocampal slices (P35 or P36). Clozapine decreased exploratory activity in WKY, consistent with antagonism of dopamine D4 and α(1)-adrenoceptors reducing the behavioural response to novelty. Clozapine also increased anxiety-related behaviour of WKY. However, clozapine did not affect SHR, suggesting that genetic predisposition may play a role in determining clozapine's behavioural effects. WKY have been shown to have higher levels of dopamine D4 receptor expression in the PFC than SHR, which may be a reason for their elevated response to clozapine. SHR released more [(3)H]noradrenaline from PFC and hippocampal slices in response to glutamate- and elevated potassium-stimulation, compared to WKY and SD rats. However clozapine treatment did not affect glutamate-, GABA- or depolarization-evoked release of [(3)H]noradrenaline.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Anxiety; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Clozapine; Exploratory Behavior; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Injections, Intraperitoneal; Male; Motor Activity; Norepinephrine; Potassium; Prefrontal Cortex; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Adolescent; Adult; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Internet; Pertussis Vaccine; Safety; Seizures; Selective Serotonin Reuptake Inhibitors; Spasms, Infantile; Suicide

Selective attention deficit, characterised by the inability to differentiate relevant from irrelevant information, is considered to underlie many cognitive deficits of schizophrenia, and appears to be only marginally responsive to treatment with current antipsychotics.. We compared the activity of the putative atypical antipsychotic SSR181507 (a dopamine D(2) receptor antagonist and 5HT(1A) receptor agonist) with reference compounds, on disturbances of novelty discrimination in a social context in rats, a behavioural paradigm that putatively models selective attention deficit.. A first (familiar) juvenile rat was presented to an adult rat for a period (P1) of 30 min. A second (novel) juvenile was then introduced at the end of P1 for a period (P2) of 5 min. The ability of the adult rat to discriminate between the two juveniles, presented at the same time, was evaluated by measuring the ratio of the time spent in interaction with the novel vs the familiar juvenile during P2.. Adult rats spent more time exploring the novel than the familiar juvenile. This novelty discrimination capacity was disrupted by: (1) parametric modification of the procedure (reduction of time spent in contact with the familiar juvenile during P1); (2) acute injection of psychotomimetics that are known to induce schizophrenia-like symptoms in humans, such as phencyclidine (PCP; 3 mg/kg, i.p.) and d-amphetamine (1 mg/kg, i.p.) and (3) neonatal treatment with PCP (three injections of 10 mg/kg, s.c.), a model based on the neurodevelopmental hypothesis of schizophrenia. The potential atypical antipsychotic SSR181507 (0.03-3 mg/kg, i.p.) and the atypical antipsychotics clozapine (0.1-1 mg/kg, i.p.) and amisulpride (1-3 mg/kg, i.p.) attenuated deficits in novelty discrimination produced by parametric manipulation and by acute or neonatal treatment with PCP. The typical antipsychotic haloperidol (up to 0.3 mg/kg, i.p.) attenuated only deficits in novelty discrimination produced by parametric modification.. Collectively, these results suggest that SSR181507 can alleviate disturbances of novelty discrimination in a social context in rats, and that this paradigm may represent a suitable animal model of selective attention deficits observed in schizophrenia.

Topics: Age Factors; Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Clozapine; Dextroamphetamine; Dioxanes; Discrimination, Psychological; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; Imipramine; Injections, Intraperitoneal; Male; Phencyclidine; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Recognition, Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Social Behavior; Tacrine; Tropanes