Neuropharmacological profile of selected areas responsible for inhibition of P50 wave: from P50 wave to off-label treatment of schizophrenia Přemysl Vlček, Barbora Kohútová, Jakub Polák, Martin Brunovský
[email protected]
National Institute of Mental Health Introduction
Wave P50, sensory gating
Schizophrenia is often associated with impaired sensory gating, i. e. the process of sensory inhibition of fast successive stimuli, which can be measured using the P50 evoked potential. Its specific neurophysiological properties might explain the disinhibition processes and their pharmacological alternation. While the classic antagonists of D2 receptor do not affect P50, antagonists of 5-HT3 receptor (clozapine, setrons) and agonists of adrenergic α2A receptor (clonidine, guanfacine) show a promising inhibition and therapeutic effect. The aim of this poster is to present some drugs affecting the specific receptors (5-HT3, CHRNA7, α2A) and the differences in their mechanism impacting on the P50. Freedman R, Olincy A, Ross RG, Waldo MC, Stevens KE, Adler LE, et al. The genetics of sensory gating deficits in schizophrenia. Curr Psychiatry Rep. 2003;5(2):155-61.
Evoked potential P50 is achieved thanks to an acoustic stimulus (beep sound), followed after 50 ms by an EEG response (positive peak). If in 500 ms after the first sound (S1) comes another stimulus (S2), the so-called sensory gating should appear. It is manifested as decrease in amplitude (peak highth) of S2. It is due to neuronal inhibition processes that should prevent the sensoric system from being ineffectively overloaded with redundant stimuli with no new information. The ratio of amplitudes (S2/S1) or their difference (S1-S2) represents the sensory gating ratio (SGR). Patterson JV, Hetrick WP, Boutros NN, Jin Y, Sandman C, Stern H, et al. P50 sensory gating ratios in schizophrenics and controls: a review and data analysis. Psychiatry Res. 2008;158(2):226-47.
Comparison of grand averaged P50 waves in 21 healthy subjects and 16 schizophrenic patients measured at the time when acoustic hallucinations occured. The black and red lines represent a response to the first and second stimulus (S1, S2), respectivelly. The authors of the study also confirmed a dependency between lower SGR score (S2-S1) and higher PSYRATS score, which is a measure of psychoticity. The absence/presence of acoustic hallucations during the study had no effect. In coclusion, impairment in P50 inhibition is not dependent on the actual psychotic state, hence is rather a trait marker). Source: Smith DM, Grant B, Fisher DJ, Borracci G, Labelle A, Knott VJ. Auditory verbal hallucinations in schizophrenia correlate with P50 gating. Clin Neurophysiol. 2013;124(7):1329-35.
P50 in schizophrenia An inhibition deficit demonstrated as low SGR has been repeatedly shown in schizophrenia. Based on a meta-analytic study it has been confirmed, that lower SGR, indenpendent on lower S1 response, is characteristic for schizophrenia. Lower S1 response in schizophrenia is associated with an impairment of sensorial iput. Chang WP, Arfken CL, Sangal MP, Boutros NN. Probing the relative contribution of the first and second responses to sensory gating indices: a meta-analysis. Psychophysiology. 2011;48(7):980-92.
Neuroanatomical correlates of P50 wave
Influencing P50 wave through hippocampal inhibitory system
Influencing P50 wave through strengthening of PFC function
The hippocampus plays a role of a neural memory comparator evaluating correspondence between S1 and S2. The inhibition of S2 is controlled through inhibitory interneurons with α7 nicotine-acetylcholine (CHRNA7) receptors. Genetic deviation affecting the production of CHRNA7 (functionality and sensitivity) has been demonstrated in schizophrenia, specifically dinucleotide polymorphism on chromosome 15 (15q13-14). Hajos M, Rogers BN. Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr Pharm Des. 2010;16(5):538-54.
Pharmacology of hippocampal inhibitory system 3-[(2,4-dimethoxy) benzylidenanabasein (DMXB-A) is a natural alkaloid with a potential of partial antagonism of CHRAN7. The left figure shows averaged P50 curve in 12 schizophrenic patients on antipsychotic medication. Stronger inhibition of S2 was accomplished with a lower dose of DMXB-A. In regards to cognitive performance DMXB-A influenced the best attention and recollection of a figure or series of words with a 20-minute delay (delayed memory index). These results were considerably better than after administration of nicotine (effect size for attention: nicotine/DMXB-A 0.25/2.17). Better effect for DMXB-A compared with nicotine was also demonstrated for wave S2 suppression. Source: Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006;63(6):630-8.
CLOZAPINE is an atypical antipsychotics capable (similarly to related OLANZAPINE) of antagonism on 5-HT3 receptors leading to an increased level of acetylcholine in the hippocampus. Both drugs demonstrably improve (yet clozapine more) SGR measured by P50. Freedman R. alpha7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. Annu Rev Med. 2014;65:245-61.
ONDANSETRONE is the first clinical agent of setrons, drugs primarly designated for antiemetic treatment through disruption of afferent vagus nerve fibres on the gastric mucous membrane. Setrons are strong antagonists of 5-HT3 receptors (e.g. CLOZAPINE Ki (5-HT3) = 241nM, while GRANISETRON Ki (5-HT3) = 1.41nM (in the human hippocampus)). TROPISETRONE, apart from 5-HT3 antagonism (Ki = 5. nM), also shows distinct antagonism on α7 nicotine-acetylcholine receptors (Ki = 6.9nM).
SETRONS considerably streghten SG measured by P50 in non-smokers. When added to antipsychotics (except CLOZAPINE), the setrons show solid therapeutic effect. Elimination half-time is no more than 10 hours (the longest el. half-time of 40 hours is for PALONOSETRONE). Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, et al. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res. 2005;76(1):67-72.
The figure above was taken from a study analyzing sources (dipoles) of the P50 wave in healthy controls and patients with schizophrenia. Hippocampal activity increased with increasing SGR in the healthy subjects but not schizophrenic patients. The key finding was that higher SGR in schizophrenia was related to activity in the dorsolateral prefrontal cortex (DLPC). In general, schizophrenia is associated with low SGR, which is in concordance with hippocampal inhibitory systems impairment and decrease of the overall volume and connectivity of the hippocampus. The above average SGR value observed in the schizophrenic patients might have been due to increased attention to S1 stimuli, which is a function controlled among others by the PFC. Thus, the automatic, implicit inhibitory process mediated by the hippocampus is impaired in schizophrenia. However, this inhibition failure may be compensated by increased activity of a regulated inhibitory system of the PFC which can be achieved by drugs or psychoeducation. Picture sourceu: Williams TJ, Nuechterlein KH, Subotnik KL, Yee CM. Distinct neural generators of sensory gating in schizophrenia. Psychophysiology. 2011;48(4):470-8. Yee CM, Nuechterlein KH, Morris SE, White PM. P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects. J Abnorm Psychol. 1998;107(4):691-8.
Clinical implications of supressors of P50 in therapy of schizophrenia When setrons are added to antipsychotics they improve the negative symptoms of schizophrenia. In a meta-analysis of six studies conducted on 311 subjects in total, different combinations of three setrons with risperidone or ondansetrone were researched (Kishi, 2014). All the three setrons showed statistically significant effectiveness in decrease of negative symptomatology (N = 261; SMD = −1.10, CI = −1.82- − 0.39; p = 0.002) measured by PANSS. A good effect was demonstrated for a combination of ondansetrone with haloperidol. Augmentation of setrons was very well supported (constipation was the most common side-effect). Kishi T, Mukai T, Matsuda Y, Iwata N. Selective serotonin 3 receptor antagonist treatment for schizophrenia: meta-analysis and systematic review. Neuromolecular Med. 2014;16(1):61-9.
Freedman et al. (1982) reported their clinical experience with CLONIDINE. They found that it had the same characteristics as the classic antipsychotics. The advantage of clonidine administration is that it bypasses tardive dyskinesia and neuroleptic malignant syndrome. The pro-cognitive effect of clonidine proves successful wherever PFC dysfunction is expected. Freedman R, Kirch D, Bell J, Adler LE, Pecevich M, Pachtman E, et al. Clonidine treatment of schizophrenia. Double-blind comparison to placebo and neuroleptic drugs. Acta Psychiatr Scand. 1982;65(1):35-45.
CASE STUDY: A 28-year old patient with schizophrenia suffering from serious hallucinations and delusions together with flatten thinking and impaired communication was successfully treated at St. Anna’s psychiatric clinic in Paris. The patient did not respond at all to clozapine and insufficiently to a pharmacologically very interesting combination of aripiprazol and clozapine (communication improved but the hallucinations were still there). The auditory hallucinations partly retreated after a second series of transcranial magnetic stimulation applied temporally. When the hallucinations reappeared with extremely strong intensity, a combination of clozapine+aripiprazol+clonidine (0,75 mg/day) was used which led to significant remission. The hallucinations got reduced and their affective component dropped; the same was observed for delusional thoughts. The patient then started playing football, read books, and his communication with parents improved. It seems that clonidine in combination with the mentioned antipsychotics proved high treatment effectiveness. Dardennes RM, Al Anbar NN, Rouillon F. Successful augmentation of clozapine-resistant treatment of schizophrenia with clonidine. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(4):724-5.
Project registration number: CZ.1.05/2.1.00/03.0078 Name of the project: National institute of mental health (NIMH)
Activity of PFC is controlled by the level of noradrenaline (NA). Switching on/off of the PFC is mediated thanks to α2A and α1 adrenergic receptors with different sensitivity to NA (56nM vs 330nM). Optimal level of NA (concentration on a task) activates α2A receptors – the PFC is involved. Higher level of NA (stress load) activates α1 receptors, which turn off the PFC (disconnection of controlled inhibition, engagement of orientation behavior, preparation for a flight-or-fight reaction). Disconnection of the PFC leads to higher activation of posterior cortical areas and subcortical systems. These regions are under the controlled inhibition through their connection with the PFC. A key component of the optimal control of inhibition is the functional and effective connection between the PFC and locus coeruleus. Gi, Gs, Gq – G-proteins associated with adrenergic receptors; NE – noradrenaline (norepinephrine); AC – adenylyl cyclase; PLC – phospholipase C; IP3, inositol 1,4,5 – triphosphate; DAG – diacylglycerol.) CLONIDINE is an antagonist of α2A receptors, hence increasing the PFC function. In a study from Denmark it showed a significant inhibitory effect on the P50 wave (S2) in patients with schizophrenia. Picture source: Ramos BP, Arnsten AF. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007;113(3):523-36. Oranje B, Glenthoj BY. Clonidine normalizes levels of P50 gating in patients with schizophrenia on stable medication. Schizophr Bull. 2014;40(5):1022-9. Arnsten AF. Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. Int J Dev Neurosci. 2011;29(3):215-23. Arnsten AF. Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl). 2004;174(1):25-31.
Pharmacology of PFC inhibitory system CLONIDINE is a non-selective agonist of α2A receptors with demonstrable antipsychotic, antimanic, and pro-cognitive effects. Since the 80’s its main off-label potential recognized in psychiatry is management of positive symptoms of schizophrenia, restlessness, brachial aggression, and sympathetic breakdown during withdrawal syndromes. Long-term administration brought a pro-cognitive effect in Korsakoff’s syndrome. It enforces SGR measured by the P50 wave. GUANFACINE is a selective α2A agonist, which interferes 10 times less with the locus coeruleus compared with clonidine. The main indication for guanfacine is an impulsive form of ADHD, it keeps some sympatolytic effect (yet lower than clonidine). In the future therapy of psychosis it might be of use for improvement of cognitive performance and behavioural profile in those schizophrenic patients who manifest milder forms of impulsivity. It seems promising for schizophrenia treatment to use mutually ballanced doses of guanfacine and a retarded form of D1 agonist DIHYDREXIDINE. Arnsten AF, Wang MJ, Paspalas CD. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron. 2012;76(1):223-39. Ramos BP, Arnsten AF. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007;113(3):523-36. Rosell DR, Zaluda LC, McClure MM, Perez-Rodriguez MM, Strike KS, Barch DM, et al. Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder. Neuropsychopharmacology. 2015;40(2):446-53. Mu Q, Johnson K, Morgan PS, Grenesko EL, Molnar CE, Anderson B, et al. A single 20 mg dose of the full D1 dopamine agonist dihydrexidine (DAR-0100) increases prefrontal perfusion in schizophrenia. Schizophr Res. 2007;94(1-3):332-41.
