The+Neuropathology+of+Schizotypal+Personality+Disorder

Adelaida Kolaj 997700242
** The Neuropathology of Schizotypal Personality Disorder ** toc

=Introduction:= Schizotypal Personality Disorder is a multifaceted constellation of maladaptive characteristics distinguished by factors such as pervasive cognitive disruption and disorganization, restricted affect, interpersonal anxiety and conconformative tendencies, paranoid ideas as well as aberrant perception which often but not always involves delusional states, auditory and visual hallucinations and transient quasi-psychotic episodes (1). SPD prognosis shows a high level of correlation with that of Schizophrenia, and although the DSM-IV categorizes it under Cluster A Axis II eccentric personality disorders, the ICD-10 classifies it as Schizophrenia Spectrum Disorder due to similarity in clinical manifestation and mechanisms of neuropathology. Causation is believed to be a complex convolution of genetic, biochemical, neurobiological factors(1). New research has implicated the role of COMT, DNMT1, L-serine, frontal lobe and striatal/pallidal and limbic circuits, and mesolimbic dopaminergic neurotransmission--thus providing possible psychopharmacological insight, aiding in efficient and correct diagnosis, and alleviating negative symptoms of affected individuals.

=1. Neurobiological mechanisms:= Neurobiological mechanisms for the observed pathology have been proposed based on findings implicating several key determinants:

i. PSAT1, the L-Serine Pathway and NDMAR Co-agonists
In 2011, Ozeki et al found a chromosomal translocation disrupting PSAT1 lead to aberrant L-serine expression in schizotypal individuals (2). PSAT1, which is in close proximity to locus 3q13.12 and 9q21.2 and thus affected by this chromosomal break, codes for enzymes essential in the L-serine synthesis cascade; L -serine is in turn responsible for the production of NMDA receptor co-agonists glycine and D-serine. Serum glutamine and L-serine deviated in schizotypal individuals in comparison to control unaffected individuals as determined by HPLC (2). As observed in particularly astrocytes, this reduction in levels of relevant amino acids is detrimental to long term potentiation and NDMAR-dependent plasticity of local excitatory synapses: reduction or depletion of D-serine and glutamate result in a blockade of LTP as these co-agonists act as modulators of Ca-mediated glutaminergic neurotransmission(3). This anomaly can have behavioural manifestations. Decreased signalling at NDMA receptors is linked to the etiology of schizotypal personality disorder and correlates to observed hyperactivity, compromised hippocampal/spatial memory, and increased anxiety (4).

ii. COMT VAL158MET and PFC Dopaminergic Circuits
A catechol-o-methyltransferase functional polymorphism at codon position 158 resulting in Valine rather than Methionine impairs dopaminergic prefrontal circuitry and thus executive cognition, working memory and inhibition of prefrontal 'noise' as detected by the prepulse inhibition test for 'sensorimotor gating' (5). The polymorphism is correlated to schizotypy with a statistical significance of P=0.01, with individuals homozygous for the Val/Val allele rating higher in self-reported scores on the spectrum of severity (6). The COMT enzyme is responsible for the catabolism of catecholamines such as dopamine, adrenaline and noradrenaline in cortical synaptic clefts, primarily those of the prefrontal cortex and hippocampus. Val/Val results in elevated enzymatic activity of up to 40% in comparison to homozygous methionine and consequentially reduced PFC dopamine levels and dopaminergic signalling (6). Lower levels of prepulse inhibition are seen in Valine158 homozygous individuals and several memory and cognitive tasks in addition to PPI determine deficits in attention processing, working memory, sensory filtering, executive fragmentation as well as PFC baseline dopaminergic neurotransmission. To corroborate the aforementioned findings, Giakoumaki et al administered treatment of Tolcapone, a nonstimulant cortical COMT antagonist and observed a PPI increase of up to 60% in Val/Val subjects with a significance of F(1,11)=14.1, p<0.003 (6).

iii. Striatal Dopaminergic D2/D3 Receptors and Schizotypal Profile
In addition to the PFC, PPI is determined by stratal/pallidal, and pontine signaling circuitry such that extrapolatioin of cortical COMT activity has led to mesolimbic implication in a model that postulates that Val/Val indviduals have increased phasic/pulsatory dopaminergic activation in the nuccleus accumbens: such individuals have low levels of activity  in the startle inhibiting pedunculopontine tegmental nucleus and thus (have) greater PPI levels (6). Hyperactivity observed in striatal dopamine is correlated to increased dopaminergic uptake mediated by elevated levels of mesolimbic high affinity/hypersensitive D2 and D3 receptors. Receptor availability was determined using [123I] iodobenzamide SPECT; a positive correlation with self-reported Schizotypal Personality Questionaire (SPQ) scores was observed in 50 volunteers exhibiting schizotypal features (6). Diagram 1: Reference (6) Percent Prepulse Inhibition for two Genotypes.

=2. Basis for Aberrant Perception/Transient Psychotic Episodes:= Schizotypal disorder morbidity is often, but not always characterized by transient states of quasi-spychosis, abnormal ruminations/perceptions, episodic breaks from reality, as well as auditory and visual hallucinations--either stress induced and externally unprovoked--ranging in a spectrum of affect and severity.

i. Epigenetics: Preferential Expression of DNMT1 and Resulting GAD 67 Isoform Deficits
In a 2004, a post-mortem study conducted by Veldic et al elucidated the role of epigenetics in psychosis. In GABA-secreting interneurons in cortical layers I,II, and IV of subjects prone to psychosis, DNA-methyltransferase 1 is upregulated and preferentially expressed such that it enhances hypermethylation of CpG promoter regions thus down-regulating downstream genes (7). Consequentially, in Brodmann's Area 9, 10, 17 and the caudate nucleus, glutamic acid decarboxylase 67 was found to exist at lower levels, in addition to there being 20% fewer neurons testing positive for GAD67 mRNA as determined by in situ hybridization. To ensure these epigenetic changes were a characteristic of psychosis, the sample population of cohorts included Schizoaffective, Schizophrenia Spectrum, and Bipolar with and without psychosis. Density of neurons positive for DNMT1 is increased by 37% in comparison to non psychiatric cohorts--seen in GABAergic interneurons but not glial or pyramidal cells in immunohistochemistry studies conducted with Neuron-Specific Nuclear Protein (7). Deficits in reelin-- an integrin modulator implicated in synaptic plasticity which is released by GABAergic neurons--are also detected. The function of the 67 kDa isoenzyme in interneurons in dorsolateral prefrontal cortex is to convert glutamic acid to γ-amino butyric acid (GABA), the main inhibitory neurotransmitter. The reduction in GAD thus results in perurbation in circuitry and impaired inhibition, leading to the proposal of a mechanism of sensory overstimulation caused by overactivity of AMPAR and NMDAR-mediated glutaminergic transmitter as the basis for psychosis. Further research implicates GAD67 as acomponent in the CREB-modulated BDNF-TrkB pathway (8), and correlates its deficiency to glutamate-dependent neuronal excitotoxicity and escalated reduction of GAD67 mRNA (9). Figure 2: Reference (8):’’ TrkB signaling in neocortical interneurons is necessary for normal GABAergic protein and mRNA expression levels, particularly of the synaptically enriched protein GAD65’’



Figure 3 Reference (9): ‘’ Glutamate excitotoxicity decreases viability of cultured hippocampal GABAergic neurons. ’’

=3. Neuro-Psychopharmacology:= Psychotherapeutic intervention is often reserved for more severe and maladaptive cases of schizotypy and although no drug treatment formulated specifically for SPD is currently marketed, negative aspects of symptomatology are managed through the administration of antidepressants, antipsychotics, stimulants, anxiolytics, and mood stabilizers/anticonvulsants alone or in conjunction (10).

i. Antidepressants:
a. Hyperforin and Target-Specific Activation of CREB-BDNF-TrkB Signalling Cascade Hyperforin, isolated as the psychoactive molecule in Hypercium Perforatum has been shown to have antidepressive properties and neurogenerative qualities tissue specific for the cortex. Its mechanism of action involves enhancement of the aforementioned pathway of brain-derived neurotrophic factor (BDNF) and its receptor TrkB as modulated by the calcium, protein kinase A, cyclic adenosine monophosphate response element binding-protein (CREB), and phospho-CREB (11). The effects of hyperforin were monitered both in in vitro culture and administered intraperotoneally in adult mice at a daily dose of 4 mg/kg, Western Blot analysis was performed for all relevant molecules and the findings were as follows: Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade (11).Cortical BDNF receptor TrkB was enhanced; in addition, observed antidepressive properties are due to hyperforin-induced elevation of Ca and Na influx through TrkB as well as transient cation channel TRPC6 to reduce amine transmitter re-uptake locally (12). (Insert Diagram 4)

ii. Antipsychotics:
b. Olanzapine and Risperidone: Assessing Improvements in Cognitive Function and Neuropathology Olanzapine is a thienobenzodiazepine antagonist whose pharmacokinetic mechanism of action involves a blockade of striatal/limbic dopamine receptors as evidenced by in vitro studies where receptor occupancy is found to be between 0.4 to 0.9 varying with dosage and mode of administration (13 diagram). Risperidone, more specifically its 9-hydroxyrisperidone metabolite, is a serotonin 5-HT2A antagonist and high-affinity D2 binder (14). Both drugs are second generation atypical antipsychotics commonly prescribed to treat states of delusional psychosis and mania. Administration of Olanzapine and Risperidone to a sample of one hundred cohorts syndromic for first-episode psychosis Schizophrenia Spectrum Disorders including Schizotypal Personality Disorder, Schizoaffective Disorder and Attenuated Psychosis Syndrome, enhanced cognitive efficiency-- reducing global deficits and executive impairments in 30% of patients. In a 2009 randomized, open label, longitudinal study, psychopathological evaluations were performed at baseline prior to treatment and after; each patient received 2.5 mg of Risperidone and 5 mg of Olanzapine for a 6-month period after which neurocognitive function was assessed to be improved by 54% (15).

Figure 5 Reference (13): ‘’Observed and predicted olanzapine concentrations and D2RO //vs//. time. ’’

iii. Anxiolytics:
a.Citalopram and Persistent Psychosocial Anxiety Induced CREB/CRE Activation In //Psychotherapeutic and Pharmacologic Treatment of Schizotypal// //Personality Disorder,// Nathanson et al found Citalopram, a Selective Serotonin Reuptake Inhibitor to be effective and well-tolerated in treating anxiety-like symptoms associated with SPD (10). Although traditionally marketed as an antidepressant, Citalopram, stereochemically racemized into Citalopram hydrobromide and escitalopram, has anxiolytic properties commonly used in pharmacological management of anxiety, stress, and panic. Boer et al proposed that the SSRI can mitigate the effects of the CRE/CREB-mediated gene transcription pathway implicated as a core neurological facet of prolonged psychosocial anxiety(16). Inhibition of serotonin reuptake causes reduction in stress-activated CREB function in the hippocampus, colliculi, PFC, and hypothalamus, as observed in mice transgenic for the CRE-luciferase reporter gene subjected to 25 days of repeated stress; visualization was facilitated by immunoblotting brain homogenates for CREB versus P-CREB. Analysis revealed that stress-induced phosphorylation of CREB at serine-119 paralleled CRE-dependent expression of genes associated with chronic psychosocial anxiety—a phenomenon reversed with citalopram administration which reduced P-CREB levels to baseline (16).

Conclusively, Schizotypy is a multidimensional condition involving many correlative/causative factors such as, among others, epigenetics, COMT genotype variance, PSAT1 gene, as well as mesolimbic, striatal, and prefrontal dopaminergic pathways. Further research attempting to address these factors as therapeutic targets would be beneficial in mitigating Schizotypal symptomatology.

=References= 1.Peskin M, Raine A. Schizotypal Personality Disorder. Corsini Encyclopedia of Psychology 2010 January; 1-2. Doi:10.1002/9780470479216.corpsy0823.

2. Ozeki Y, et al. A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: Altered L-serine level associated with disruption of PSAT1 gene expression.Neuroscience Research 2011 February; 69(2):154-160. Doi: 10.1016/j.neures.2010.10.003.

3. Hennenberger C, Papouin T, Oliet S, Rusakov D. Long-term potentiation depends on release of D-serine from astrocytes. Nature International Weekly Journal of Science 2010 January; 463: 232-236. Doi: 10.1038/nature08673.

4. Basu A, et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Molecular Psychiatry 2009 July; 14: 719-727. Doi: 10.1038/mp.2008.130. 5.Schurhoff F, et al. Schizotypal dimensions: An intermediate phenotype associated with the COMT high activity allele. Americal Journal of Medical Genetics 2007 January; 144B(1):64-68. Doi:10.1002/ajmg.b.30395. 6.Giakoumaki S, Roussos P, Bitsios P. Improvement of prepulse inhibition nad executive function by the COMT inhibitor tolcapone depends on VAL158MET polymorphism.Neuropsychopharmacology 2008 June; 33: 3058-3068. Doi: 10.1038/npp.2008.82.

7.Veldic M, Guidotti A, Maloku E, Davis J, Costa E. In psychosis, cortical interneourons overexpress DNA-methyltrasferase 1. PNAS 2005 January; 102(6). Doi: 10.1073/pnas.0409665102

8. Sanchez-Huertas C, Rico B. CREB-dependent regulation of GAD65 Transcription by BDNF\TrkB in cortical interneurons. Cerebral Cortex Oxford Journals 2011; 21(4): 777-788. Doi:10.1093/cercor/bhq150.

9. Baptista M, et al. Role of the proteasome in excitotoxicity-induced cleavage of glutamic acid decarboxylase in cultured hippocampal neurons. PLoS ONE 2010; 5(4): e10139. Doi:10.1371/journal.pone.0010139.

10. Nathanson B, Jamison S. Psychotherapeutic and pharmacologic treatment of schizotypal personality disorder: the heuristic utility of stressing function over form. Clinical Case Studies 2011 October; 10(5):95-407. Doi:10.1177/1534650111427076.

11. Gibon J, Deloulme J, Chevallier T, Ladaveze E, Abrous D, Bourdon A. The antidepressant hyperforin increases the phosphorylation of CREB and the phosphorylation of TrkB in a tissue-specific manner. The International Journal of Neuropsychopharmacology;2012 January. Doi:DOI: 10.1017/S146114571100188X.

12. Leuner K et al. Hyperforin—a key constituent of St John’s Wort specifically activates TRCP6 channels. The Journal of the Federation of American Societies for Experimental Biology 2007 December; 21(14): 4101-4111. Doi:10.1096/fj.07-8110com

13. Johnson M, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats. Pharmaceutical Research 2011 June; 28(10): 2490-2504. Doi:10.1007/s11095-011-0477-7.

14. Davies M, Conley Y, Roth B. Functional SNPs in genes encoding the 5-HT2A receptor modify the affinity and potency of several atypical antipsychotic drugs. Biological Research for Nursing 2010 January; 13(1):55-60. Doi: 10.1177/1099800409358760.

15.Cuesta, M, et al. Cognitive effectiveness of olanzapine and risperidone in first-episode psychosis. The British Journal of Psychiatry 2009; 194:439-445. Doi:10.1192/bjp.bp.108.055137.

16. Boer U, et al. A common mechanism of action of the selective serotonin reuptake inhibitors citalopram and fluoxetine: Reversal of chronic psychosocial stress-induced increase in CRE/CREB-directed gene transcription in transgenic reporter gene mice. European Journal of Pharmacology 2010 May; 633(1-3): 33-38. Doi: 10.1016/j.ejphar.2010.01.016.