[Why do schizophrenic patients smoke?].

Psychiatrische Poliklinik, Inselspital, Bern, Schweiz.
Der Nervenarzt (Impact Factor: 0.79). 04/2005; 76(3):287-94.
Source: PubMed


Patients suffering from schizophrenia are known to show an increased prevalence of nicotine addiction. The aim of this paper is to elucidate the relationship between schizophrenia and (chronic) use of nicotine. Nicotine seems to improve cognitive functions critically affected in schizophrenia, in particular sustained attention, focused attention, working memory, short-term memory, and recognition memory. Furthermore, several studies using evoked potentials (P50 paradigm) and prepulse inhibition of the acoustic startle reflex suggest that deficient preattentive information processing, a core feature of schizophrenia illness, is improved following treatment with nicotine. Smoking can also improve extrapyramidal secondary effects of antipsychotic medication and it induces cytochrome P4501A2, an enzyme system involved in the metabolism of several antipsychotics. There is substantial evidence that nicotine could be used by patients with schizophrenia as a "self-medication" to improve deficits in attention, cognition, and information processing and to reduce side effects of antipsychotic medication. Possible pharmacotherapeutic approaches for the regulation of abnormal neurotransmission at nicotinic acetylcholine receptors are discussed.

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    ABSTRACT: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by delayed or absent speech, impairments in social interaction and in communication, and repetitive behaviors and restricted interests. The relationships between ASD, schizophrenia (SZ), and bipolar disorder (BP) are not clear. Although characteristic features of SZ and BP such as delusions, hallucinations, euphoria, or melancholia are usually not present in people with ASD, there are also a few common psychopathological dimensions. For example, catatonia has been described in ASD, SZ, and BP (Abrams and Taylor, 1976; Dhossche, 1998; Realmuto and August, 1991). Moreover, family studies have reported increased rates of schizophrenia-like and affective disorders (Larsson et al., 2005). Parental schizophrenia-like psychosis and affective disorder were significant risk factors for autism in offspring in a nationwide Danish case-control study of 698 children diagnosed with autism between 1972-1999 (Larsson et al., 2005). Relative risks were 3.44, 95% CI 1.48-7.95 and 2.91, 95% CI 1.65-5.14, for parental schizophrenia-like disorder and affective disorder respectively. Other significant variables were breech presentation (RR = 1.63), low Apgar score at 5 minutes (RR = 1.89), and gestational age at birth less than 35 weeks (RR = 2.45). Weight for gestational age, parity, number of antenatal visits, parental age, or socioeconomic status were not significant risk factors. These findings support that perinatal factors and parental psychopathology are associated with risk of autism. It remains an open question whether perinatal adversity was due to environmental factors, factors associated with autism in the fetus, or a combination of these and possibly other (unmeasured) variables. A parsimonious explanation is that the genetic make-up of the fetus interferes with intrauterine development leading to increased risk for perinatal complications. However, perinatal factors and parental psychiatric disorder seemed to act independently in this study. This suggests two sets of autism-related etiologies (i.e., a genetic set and an obstetric set). These findings need to be replicated in other samples. However, the Danish study will be hard to match because of its almost complete ascertainment of cases, high quality of information on all risk factors, and prospective design. In any case, further family psychiatric studies assessing psychotic disorders, including catatonic subtypes, as risk factors for autism are warranted. Previous studies have typically not separated out catatonic subtypes of schizophrenia, affective disorder, or other psychotic disorders. A subtype of unsystematic SZ is characterized by periodic catatonia where acute psychotic episodes are followed by remission. These disorders have shown strong heritabilities with some 15 to 20 genes expected to be involved in ASD (Spence, 2004), while a major gene effect is predicted for catatonia (Stober et al., 1995). The search of the genes related to these psychiatric disorders has shown significant progress in the recent years with the identification of some strong candidates for SZ such as the dystrobevin binding protein 1 (Straub et al., 2002) and the neuregulin 1 (Stefansson et al., 2002) genes. Numerous other genes have been tested for these disorders with more or less success. However, from the literature, it is obvious that the same genes and biological pathways could be shared among the disorders. A striking example is the catechol-O-methyltransferase gene (COMT) on chromosome 22q11.2. COMT encodes a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain and this role in the degradation of catecholamine neurotransmitters may suggest a general involvement of COMT in psychiatric diseases. The COMT protein shows two forms, the membrane-bound longer form being the main form expressed in the brain, while the soluble shorter form is expressed in other tissues such as the spleen and the liver. A common COMT polymorphism (Val108/158Met) in exon 4, changing a valine for a methionine at the position 108 or 158 of the short and the long forms, respectively, affects significantly the protein abundance and the enzyme activity, but not mRNA expression (Chen et al., 2004a; Egan et al., 2001; Shield et al., 2004). Positive association of Val108/158Met with SZ have been generally reported (Chen et al., 2004b; Egan et al., 2001; Glatt et al., 2003a; Sazci et al., 2004; Wonodi et al., 2003), as weaker evidence in a recent meta-analysis (Fan et al., 2005), and in a study of Korean SZ inpatients (Park et al., 2002). COMT Val108/158Met polymorphism has also been associated with schizotypy (Avramopoulos et al., 2002) but not cognition (Stefanis et al., 2004), with prefrontal neurocognitive function in healthy (Rosa et al., 2004) but not SZ individuals (Ho et al., 2005; Rosa et al., 2004), with the 22q11.2 deletion syndrome (Bearden et al., 2004), with anxiety (Enoch et al., 2003; McGrath et al., 2004), and with anorexia nervosa (Gabrovsek et al., 2004). Two SNPs located in intron 1 and in the 3′ flanking region of COMT have also been associated with a risk for SZ (Shifman et al., 2002) and for BP (Shifman et al., 2004). It has been proposed that the effect of the intron 1 SNP in SZ could come from a linkage disequilibrium (LD) with a SNP in the P2 promoter (Palmatier et al., 2004). These SNPs lowered COMT mRNA expression in anonymous postmortem brains (Bray et al., 2003), while this lower expression was not observed in the lymphocytes of SZ patients (Chen et al., 2004a). Other examples of the communality observed between mental disorders are the serotonergic and dopaminergic family of genes. For example, the serotonin transporter gene has been associated with different mental disorders including ASD (Yirmiya et al., 2001), while the dopamine receptor D2 had showed association with attention-deficit/hyperactivity disorder (ADHD), alcoholism (ALC), and Tourette's syndrome (Comings et al., 1991). We have compiled the significant results from published genome scans for six different mental disorders and observed shared chromosomal susceptibility regions among all of them (Chagnon et al. in preparation). From this first analysis, we observed that chromosome 15, particularly, shared common susceptibility regions for some disorders including ASD, SZ, BP, ADHD, and ALC. The only significant linkage results for catatonia in a subgroup of SZ were also observed on chromosome 15. In this chapter, we will present chromosomes with significant genome scan results for ASD putting an emphasis on chromosome 15 where chromosomal rearrangements and abnormalities, and candidate gene analyses will also be presented in relation to ASD and catatonia susceptibility loci. Methods: Relevant genome scan papers have been identified by a search in the PubMed database using the key words "linkage OR genome scan" AND "schizophrenia OR bipolar disorder OR autism OR catatonia OR alcoholism OR attention deficit hyperactivity deficiency OR Tourette" (Chagnon et al. in preparation). The criterion for inclusion of the results of a genome scan was a Lod score of 3.0 and greater corresponding to a P value of 0.0001 and smaller. P values of 0.05 and smaller were also included when "genome wide adjusted." From these, only chromosomes including significant susceptibility regions for ASD have been retained in the actual compilation. The chromosomal location of all the linked markers has been updated using the same and most recent version of the physical map in megabases (Mb) from the National Center for Biological Information (NCBI built 35.1). One Mb corresponds to 106 bases or nucleotides of DNA. When the location on the physical map was not available for a given marker, genetic maps in centimorgan (cM) units from Marshfield (Broman et al., 1998) have been used to determine the relative position of the marker, where one cM corresponds roughly to 1 Mb. Additionally, the cytological locations have been updated using the predictive locations (GMAP) from the Genetic Location Database (Collins et al., 1996). We have also reported for the linked markers of these chromosomes the susceptibility loci assigned by NCBI (built 35.1) where the same locus can be assigned to more then one marker. For example, four linked markers of the genome scans (D1S1631, D1S1653, D1S1679, and D1S196) are related to the Schizophrenia susceptibility 9 on chromosome 1p21.2-q24.2, while a unique linked marker (D1S484) at 1q24.1 is related to the Asperger syndrome 3. Some apparent contradictions are observed between physical and cytological locations for these susceptibility loci. For example, Autism 1 susceptibility locus at 7q31.31 is related to marker D7S486 according to NCBI ePCR result while Autism 1 was originally assigned to 15q11-q13. For chromosome 15 only, ASD and catatonia suggestive genome scan results, chromosomal rearrangements and abnormalities, and positive or negative candidate gene analyses have also been included. Results and Discussion:
    International Review of Neurobiology 02/2005; 71:419-43. DOI:10.1016/S0074-7742(05)71017-5 · 1.92 Impact Factor
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    ABSTRACT: Startle responses are attenuated by prepulse inhibition (PPI), which is considered to reflect a sensorimotor gating mechanism and is impaired in patients suffering from schizophrenia. A midbrain circuit that mediates PPI in rats has been proposed and behavioral experiments have indicated an important role of acetylcholine and GABA in inhibiting startle. We here test the hypothesis that activation of the midbrain neurons can inhibit startle signaling through a cholinergic mechanism. We have developed a brain slice that comprises startle mediating giant pontine neurons as well as midbrain mesopontine neurons required for PPI. Patch clamp recordings of startle mediating brainstem neurons combined with stimulation of sensory afferents within the startle pathway and activation of mesopontine neurons revealed a delayed inhibition of synaptic transmission 300 ms and 1 s after midbrain activation. The latter was reversed by the muscarinic antagonist scopolamine. Further, there was a shift in the paired pulse ratio 1 s but not 300 ms after midbrain stimulation. Our results show that there is a direct cholinergic projection from the proposed PPI midbrain circuit to startle mediating neurons in the brainstem and that this projection inhibits synaptic transmission in the startle pathway in a distinct time window through the activation of presynaptic muscarinic receptors. Moreover, there is indication for a different receptor that mediates inhibition through this projection in a shorter time window and is located postsynaptically. Our results contribute to the understanding of mechanisms underlying PPI, which is important for developing new targets in the treatment of disorders accompanied with pre-attentive cognitive deficits.
    Neuroscience 05/2008; 155(1):326-35. DOI:10.1016/j.neuroscience.2008.04.018 · 3.36 Impact Factor
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    ABSTRACT: Blockade of NMDA glutamate receptors with dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic-glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 06/2008; 32(4):1030-40. DOI:10.1016/j.pnpbp.2008.01.018 · 3.69 Impact Factor
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