The function of the endocannabinoid system and glial cells in vivo in patients with first episode psychosis

Psychoses are relatively common and often severely debilitating mental disorders with a multifactorial etiological background involving both psychosocial and biological factors. Previously reported associations between the endocannabinoid and immune systems, and psychotic disorders, suggest that they are involved in the etiology of psychosis. Healthy individuals were studied with the selective type 1 endocannabinoid receptor (CB1R) radiotracer [18F]FMPEP-d2, and positron emission tomography (PET), for possible demographic confounders. Radiotracer synthesis and the compound’s behaviour in blood and brain tissues, were in line with reports from previous validation studies. Females had lower availabilities of CB1R than males in 17 discrete brain regions. Separate samples of male patients with first-episode psychosis (FEP) were then studied concurrently in Turku and London, using the CB1R radiotracers [18F]FMPEP-d2 and [11C]MEPPEP respectively. Lower CB1R availability was seen in FEP as compared to healthy controls. The availability of CB1R was also inversely associated with the symptomatology of the psychoses. Translocator protein (TSPO) expression has been postulated to represent glial cell and mitochondrial functions, both of which are influenced by endocannabinoid signalling. Another sample of male and female patients with first episode psychoses was studied using PET with the selective TSPO radiotracer [11C]PBR28. Male and female FEP subjects showed globally lower availability of brain TSPO in comparison to healthy controls. Two concurrent samples of FEP individuals showed persistent elevations of the chemokine CCL22 when compared to population controls. A subgroup of patients with the highest levels of CCL22 also had aberrant levels of other cyto- and chemokines. These results indicate that the immune and brain endocannabinoid systems have become dysregulated in early psychosis. Aberrant glial cell function and/or disturbances in cell metabolism are indicated by the lower availability of TSPO.Endokannabinoidijärjestelmän ja gliasolujen toiminta ensipsykooseissa Psykoosit ovat verrattain yleisiä, vakavia mielenterveyshäiriöitä, joiden syntyyn vaikuttaa sekä psykososiaaliset että biologiset tekijät. Endokannabinoidi- ja immuunijärjestelmien yhteydet psykooseihin, sekä dopamiinijärjestelmän toimintaan, viittaavat näiden järjestelmien toimivan osana psykoosien etiologiaa. Terveiden koehenkilöiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin tyypin 1 endokannabinoidireseptorin (CB1R) merkkiaineella [18F]FMPEPd2, ja positroniemissiotomografialla (PET), mahdollisten sekoittavien tekijöiden tunnistamiseksi. Merkkiaineen tuotannon laatua kuvaavat tunnusluvut, sekä merkkiaineen käyttäytyminen veressä ja aivokudoksessa, vastasivat aiempien validointitutkimusten tuloksia. Naiskoehenkilöillä oli alhaisemmat [18F]FMPEP-d2:n jakautumistilavuudet 17 aivoalueella verrattuna miehiin. Miespuolisten ensipsykoosipotilaiden aivojen endokannabinoidijärjestelmän toimintaa tutkittiin erikseen Turussa ja Lontoossa PET:lla vastaavasti CB1R merkkiaineilla [18F]FMPEP-d2 ja [11C]MEPPEP. Molempien otosten ensipsykoosipotilailla oli alhaisemmat merkkiaineiden jakautumistilavuudet verrattuna terveisiin koehenkilöihin. Merkkiaineen sitoutumiselle vapaat CB1R:t olivat lisäksi käänteisesti yhteydessä psykoosioireiden vaikeusasteeseen. Aivojen tukisolujen ja näiden mitokondrioiden toimintaan vaikuttavat sekä endokannabinoidiviestintä, että translokaattoriproteiinin (TSPO) toiminta. Ensipsykoosipotilailla oli kauttaaltaan alhaisemmat TSPO PET merkkiaineen [11C]PBR28 jakautumistilavuudet verrattuna terveisiin verrokkihenkilöihin. Ensipsykoosipotilaiden kemokiini CCL22:n pitoisuudet olivat verrokkien pitoisuuksia korkeammat. Korkeimpia CCL22:n pitoisuuksia omaavien potilaiden immuuniviestintä poikkesi muista verrokki- ja potilastutkittavista laaja-alaisesti. Nämä tulokset osoittavat, että immuuni- ja endokannabinoidijärjestelmät toimivat poikkeavasti ensipsykooseissa. TSPO:n poikkeava toiminta viittaa siihen, että aivojen tukisolut ja/tai solujen aineenvaihdunta häiriintyvät psykooseissa

Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response

Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis

The associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC\u2009=\u200929); Early Psychosis with minimal cannabis use (EPMC\u2009=\u200925); Controls with a history of cannabis use (HCC\u2009=\u200916) and Controls with minimal use (HCMC\u2009=\u200922). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p\u2009=\u20090.003) and amygdala volume explained 36.9% (p\u2009=\u20090.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p\u2009=\u20090.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use

Structural and functional cerebral changes in patients with schizophrenia and genetic risk-allele carriers

Schizophrenia is one of the most frequent psychiatric disorders and is associated with a substantial part of worldwide disease burdon1. The clinical symptoms of patients with schizophrenia can be separated into positive symptoms such as halluciations and delusions as well as negative symptoms such as cognitive impairments, apathy, blunted affect and social withdrawal2. It has been suggested that understanding the underlying pathophysiological processes that give rise to these symptoms is a crucial step for the development of efficient treatment for schizophrenia3. In the presented work two aspects of the clinical symptomatology of schizophrenia are analyzed with respect to their potential neurobiological correlate. Following the dopamine-hypothesis, patients with schizophrenia exhibit an increase in dopaminergic neurotransmission in the striatum which might be related to the experience of positive symptoms4,5. In the first publication evidence for this dopamine-hypothesis from in-vivo neuroimaging studies was investigated in a comprehensive meta-analysis. Results are in the line with the dopamine-hypothesis and point to an increase of striatal presynaptic dopamine synthesis in schizophrenia: - Howes OD*, Kambeitz J*, Kim E, Stahl D, Slifstein M, Abi-Dargham A*, Kapur S* (2012): The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69: 776–786. * these authors contributed equally ISI Web of Knowledge: Archives of General Psychiatry (now: JAMA Psychiatry) impact factor 2012: 13.77 5-year impact factor 2012: 14.47 Ranked 3rd of all psychiatry journals The negative symptoms of schizophrenia such as cognitive impairments have frequently been associated with changes of cerebral gray matter in numerous brain regions including the hippocampus6–9. In the second publication, effects of a potential risk-gene on the hippocampus are analyzed. Results indicate reduced hippocampal structure and function in carriers of the met-allele of the BDNF polymorphism val(66)met: - Kambeitz JP*, Bhattacharyya S*, Kambeitz-Ilankovic LM, Valli I, Collier DA, McGuire P (2012): Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis. Neurosci Biobehav Rev 36: 2165–2177. * these authors contributed equally ISI Web of Knowledge: Neuroscience and Biobehavioral Reviews impact factor 2012: 9.44 5-year impact factor 2012: 9.92 Ranked 12th of all neurosciences journal

The effects of some typical and atypical neuroleptics on gene regulation : implications for the treatment of schizophrenia

The mechanisms by which antipsychotics (neuroleptics) produce their therapeutic effects in schizophrenia are largely unknown. Although neuroleptic efficacy is attributed to central dopamine D2 and/or serotonin 5-HT2 receptor antagonism, clinical improvements in schizophrenia are not seen until two or three weeks after daily neuroleptic administration. The mechanisms underlying the neuroleptic response must therefore occur downstream from initial receptor blockade and be a consequence of chronic neurotransmitter receptor blockade. The goal of the present study was to use neuroleptics with varied dopamine vs. serotonergic receptor blocking profiles to elucidate some of these intracellular post receptor mechanisms. Since the final steps of both dopamine and serotonin synthesis require the enzyme aromatic L-amino acid decarboxylase (AADC), the effects of neuroleptics on AADC gene (mRNA) expression were examined in PC12 cells and compared to their effects on the synthetic enzyme tyrosine hydroxylase (TH) and ' c-fos' (an early immediate gene [IEG]) mRNA. The neuroleptics examined did not significantly regulate AADC mRNA in PC12 cells, and only haloperidol upregulated TH and 'c-fos' mRNA. Later studies in rats showed that acute neuroleptic administration increased ' c-fos' mRNA, whereas the immunoreactivity of a related IEG (delta FosB) was increased upon chronic treatment. These studies and a subsequent dose response study demonstrated that upregulation of both 'c-fos' mRNA and delta FosB immunoreactivity was most prominent in dopaminergic projection areas including the striatum and nucleus accumbens. Because it has been suggested that neuroleptic treatment might prevent neurodegeneration in schizophrenia, the effects of neuroleptics on the mRNA expression of neuroprotective target genes of delta FosB were examined both ' in vivo' and 'in vitro'. These genes included brain-derived neurotrophic factor (BDNF), the neuroprotective enzyme superoxide dismutase (SOD), and the low affinity nerve growth factor receptor (p75). While dopamine D2 blockade unfavorably regulated BDNF and p75 mRNA, 5-HT 2 blockade either had no effect on or favorably regulated BDNF, SOD, and p75 mRNA. Thus, although little about the contribution of serotonergic blockade in the neuroleptic response was determined, dopaminergic blockade regulated IEG's and several of their target genes. Future studies will be needed to understand the role of 5-HT2 receptor blockade in the neuroleptic response

Schizophrenia, Not a Psychotic Disorder: Bleuler Revisited

Current diagnostic criteria delineate schizophrenia as a discrete entity essentially defined by positive symptoms. However, the role of positive symptoms in psychiatry is being questioned. There is compelling evidence that psychotic manifestations are expressed in the population in a continuum of varying degrees of severity, ranging from normality to full-blown psychosis. In most cases, these phenomena do not persist, but they constitute risk factors for psychiatric disorders in general. Psychotic symptoms are also present in most non-psychotic psychiatric diagnoses, being a marker of severity. Research revealed that hallucinations and delusions appear to have distinct, independent biological underpinnings—in the general population, in psychotic, and in non-psychotic disorders as well. On the other hand, negative symptoms were seen to be far more restricted to schizophrenia, have other underlying pathophysiology than positive symptoms, predict outcome and treatment response in schizophrenia, and start before the first psychotic outbreak. The current work discusses the concept of schizophrenia, suggesting that a greater emphasis should be put on cases where psychotic symptoms emerge in a premorbid subtly increasing negative/cognitive symptoms background. In those cases, psychosis would have a different course and outcome while psychosis occurring in the absence of such background deterioration would be more benign—probably having no, or a milder, underlying degenerative process. This reformulation should better drive psychopathological classification, face positive symptoms as epiphenomenon of the schizophrenia process, and dishevel stigma from schizophrenia and from delusions and hallucinations