G Protein Coupled Receptor Function in Bipolar Disorder Type - Research Proposal Example

Bipolar disorder, also called as manic depressive disorder is a serious clinical illness that causes a shift in the patient’s mood, functions and energy. The researchers have found that bipolar disorder is due to the presence of a genetic hotspot. G-protein Coupled receptors are found to play a major role in the development of bipolar disorder. Bipolar disorder is a genetic disease caused due to the mutations in the variants of the G-protein coupled receptor kinase 3(GRK3), present in the chromosome 22. The expression of the gene reduces the mood disorder symptoms. Many studies have suggested that GRK3 is the responsible gene for the bipolar disorder. The symptoms of bipolar disorder are mainly due to the mutations in the variants of the GRK3.in this study; a novel treatment method for bipolar disorder was planned and tested for the efficacy. The use of asenapine for the treatment of bipolar disorder for the people of age above 18 and Riluzole for the children are the two hypothesis put forth in this study. Rluzole is found to work with glutamate and reduce the depression of the bipolar disorder patients. Asenapine shows high affinity for a number of dopamine receptors such as D1, D2, D3 and D4, Histamine H1, receptors at an affinity rate of 8.9 ± 0.4. the efficacy of the drug was determined in this study.   G Protein Coupled Receptor Function in Bipolar Disorder Type Introduction: Bipolar disorder is a complex psychiatric disease having genetic basis. This is mainly due to the chemical imbalance bipolar disorder affects up to 3 percent of the total population. According to World Health Organization report of 2001, bipolar disorder stands fifth for the cause of disability among the adults. (Peacock, 2000). Male and female are affected by this disease in equal ratio. This disease can develop at any age and takes several years for complete development in the individual. Bipolar disorder is a family disease. It is the combination of stigma, disability and cognitive impairment. Depression causes the emergence of this disease in people. The lacks of neurotransmitters at the brain are found to be associated with the bipolar disorder. The symptoms of bipolar disorder are elevated mood, different thoughts, pressurized speech, less need for sleep, increase in the goal directed activity, poor judgment and tangential speech. (Pompili et al., 2011). Bipolar disorder is associated with long term morbidity, co morbidity, disability and increased mortality rates due to suicide accidents etc., (Peacock, 2000). G- Protein coupled receptors (GPCRs) comprises a super family of cell membrane receptors with many common features having a single polypeptide with many membrane spanning domains. GPCRS have seven transmembrane proteins with hetero-trimers. There is an alpha sub unit which binds to guanine nucleotides. GPCRs play important role in the development and regulation of cellular physiology. They participate in the diversified physiological functions and are the targets of many drugs. The ligands are very diverse such as amides, peptides, proteins, lipids, nucleotides and photons. GPCRs have many alternating signalling pathways and interact mainly with the proteins such as arrestins and kinases. 90% of the nonsensory GPCRs are present in the brain and they play many important neuronal functions. There are five dopamine receptors D1, D2, D3, D4 and D5 divided into two groups based on the sequence and functional similarities. D1 like (D1 and D5) and D2 like (D2, D3, D4). (Pompili et al., 2011).These dopamine receptors are believed to be involved in the brain disorders such as Parkinson’s disease, schizophrenia, addiction, and Huntington’s disease. The D4 receptor is activated by the dopamine receptor present in the brain. The mutations in the GPCRs have resulted in a number of diseases in human. The mutations may be activating mutations or inactivating mutations. D1, D2 are shown to have a greater interaction with the bipolar disorder. All the antipsychotic drugs block the dopamine D2 receptors and are potent antagonists of 5- hydroxytryptamine receptor 2A ( 5- HT2A). (Pompili et al., 2011). The D1 receptor at the A48G position is found to have association between the bipolar disorder and the D2 receptor. G-protein coupled receptor kinase 3 is also found to be associated with the bipolar disorder. GRK3 mRNA and protein levels were found to be very less in the bipolar disorder patients. GRK3 levels were found less in the lymphoblastoid cell lines of the bipolar disorder patients. (Manji, 2010). Six mutations present in the GRK3 gene are found to be linked with the disease. A mutation named as P-5 was found to be present in three regions in the bipolar disorder patients than the normal individuals. The study concluded that P-5 is the regulating portion of the gene. This region turns the gene on or off. The GRK3 gene is present in the chromosome 22. (Ucsdnews.ucsd.edu., 2003). When micro array technique was used to identify the level of expression of the gene, it was observed that the gene had high levels of expression with the genes from the rats exposed to a similar manic as that of bipolar disorder in human. After this a further study was conducted using the blood samples from three different independent set of families having bipolar disorder. To their surprise the results were nothing but the replicate for one another. (Ucsdnews.ucsd.edu., 2003). The twin studies are the best example for the indication of mood disorders in families. The mood disorders are present in the families and are expressed in the family members due to the genetic linkage. The linkage is higher if the offspring’s are twins. In monozygotic twins, the risk of mood disorders is three times greater than those of dizygotic twins. Depression, anxiety, social phobia and agoraphobia are found to be present in the twins having mood disorders at the same rate. (Rowland, Pedley and Merritt, 2009). Genetic effects seem to be very strong in these studies. Since no biomarker is developed to identify the genes responsible for this, intensive study is required in this area. In children, the polymorphism at the 5HTT promoter, showed higher levels of depressive symptoms. Similarly an allele of the gene for the brain derived neurotropic factor is found to have linkage with the bipolar disorder. (Rowland, Pedley and Merritt, 2009). Brain imaging studies using magnetic resonance imaging helps to study the relationship between psychiatric disorders and neuropathology. The increase and decrease in the limbic- paralimbic blood flow is strongly associated with the mood. A decreased level of prefrontal volume is found in the bipolar disorder patients. The hippocalamus was less asymmetric in the bipolar affected twins. (Noga, Vladar and Torrey, 2001). Evidences in favor of GRK3: The studies have finally concluded that GRK3 is strongly associated with the bipolar disorder. The chromosome 22q12 may contain the locus for the bipolar disorder. This region is found immediate to the region of the gene G protein receptor kinase- 3. (Barrett et al., 2005). Similarly the single nucleotide polymorphism studies using the microarray techniques have shown that GRK3 gene mutations have increased the risk for bipolar disorder. This was confirmed from the two genome wide linkage surveys. The p-5 linkage was very less at the frequency of 0.007 and too rare to explain the linkage. (Barrett et al., 2005). Another study was conducted to check whether G-384A variant has any functional effect on the GRK3 expression and transcription. For the analysis electrophoretic mobility shift assays were carried out. The transcriptional effect was also checked using the luciferase receptor system tranfected into the neuroblastoma cells invitro and in the mouse cells at the cultured cortical neurons. The presence of variation in the G-384A resulted in the reduced activity of the GRK3. The gene expression got enhanced on the presence of these variants at higher concentrations. From this study it was concluded that G-384A is the promoter region of GRK3. (Barett, Zhou and Kelsoe, 2008). Hypothesis: To find out the novel treatment method for the mania symptoms of bipolar disorder using GSK-3 as the target. To check the efficacy of Asenapine and Riluzole for the treatment of Bipolar disorder. Selective targeting of GSK3 can be used as a treatment for bipolar disorder. The main supporting document behind this is that mood stabilizer drugs used are having excellent curing rates for the disease with higher degree of manipulation for the GSK3. The second strong evidence for the use of GSK3 as the target for the cure of bipolar disorder is that it is not directly linked to the disease and the symptoms of bipolar disorder are only associated with GSK3. (Song et al., 1997). So manipulation using some treatment methods can reduce the disease and may have some improved behavioral effect. The third supporting evidence is that the manipulation of the GSK3 is found to decrease the mania like effects in both the animal models and clinical studies. Hence the manipulation of GSK3 using the novel treatment methods can cure bipolar disorder. (Song et al., 1997). Asenapine is the antipsychotic drug developed for the treatment of schizopernia and bipolar disorder. The first animal study was done in the year 1990. The study suggested the use of asenapine for antipsychotic and anxiolytic effects in dopamine and serotonin receptor antagonism. (Song et al., 1997). As the drug exhibits anti-psychotic effects, the drug can be used for the reduction of mood disorders such as depression, change of nature, pressued speech etc., Asenapine is classified under the dibenzo – oxepino pyrrole group with properties similar to the olanzapine and clozapine. (Song et al., 1997). Research plan: Tests for the efficacy of Riluzole: Riluzole is the member of benzothiazole class. Riluzole is a neuroprotective drug. Riluzole is found to bind with the tetrodotoxin- sensitive sodium channels and creates an influx on the calcium channels. The reduced influx of the calcium channels prevents the stimulation of the glutamate receptors. Riluzole is found to reduce the depressive symptoms of bipolar disorder. Hence a hypothesis to test the efficacy of riluzole was put forth. (Bensimon, Lacomblez, and Meininger, 1994). To evaluate the efficacy of riluzole, a double – blind , placebo controlled trial is set with. The drug riluzole was found effective in the adults but in children this test was not carried on so far. For this trial both boys and girls will be selected. The age limit is 9 – 17 years. (Bensimon, Lacomblez, and Meininger, 1994).The children who are having bipolar disorder are alone allowed. The history of the initial drugs must have proved not correct. Children must have a psychiatrist and primary care giver throughout the study. Children with DSM-IV bipolar disorder are given preference. The response of the children must be very minimum to the current drugs. (Bensimon, Lacomblez, and Meininger, 1994). The other criteria chosen for this study are the children should not have an IQ greater than 70, Autistic or developmental disorder should not be present, medical illness must not fluctuate, pregnant girls are not taken for the study, presence of renal ot hepatic dysfunction are not allowed for the study. The dosage of riluzole is 100 mg per day. The trial is divided onto 4 phases. In the first phase, the patients will undergo blood and urine tests. In the second phase, the patients will be away from medication. The patients will be monitored regularly for the recovery level and the treatment will be restarted if necessary. The third phase is the long phase for duration of 8 weeks in which the patients will be given riluzole or placebo randomly. Dose adjustments will be given when required. The patients who received riluzole and have improved will continue the treatment with riluzole and those who do not respond will be provided with standard medications. The placebo patients will be considered for treatment in the fourth phase. The placebo patients will be given riluzole for the next 8 weeks and then looked for efficacy. If they respond well to the drug, then they will be continuing with the drug for another 4 weeks. The drug riluzole is permitted for use by the National Institutes of Health (NIH). (Bensimon, Lacomblez, and Meininger, 1994). Similarly another study will be carried out to test the efficacy of Asenapine in the adults. Asenapine is a novel psychopharmacologic drug that is under the development for the treatment of both schizophrenia and bipolar disorder. Lithium is the traditional method of treatment for bipolar disorder, but lithium mono therapy is not accepted by many patients. (Bensimon, Lacomblez, and Meininger, 1994). Other drugs tried for the treatment of bipolar disorder are antipsychotics such as haloperidol, chlorpromazine, atypical antipsychotics such as quetapine, olanzapine, risperidone, ziprasodine, aripiprazolo and clozapine, and benzodiazepines such as lorazepam and chlorazepam. Asenapine is the second generation antipsychotic drug approved by the US food and Drug administration for the treatment of both schizophrenia and bipolar disorder. (Pompili et al., 2011). Asenapine has properties similar to that of quetapine, olanzapine and clozapine. Asenapine and many other drugs were tested for their efficacy of binding with the human receptors and the asenapine binding efficacy was found to be in the range of 8.6 pKa for serotonin 5-HT 1A, 8.4 for 5-HT2A, 5HT2B ( 9.8), 5HT2C ( 10.5), 5-HT 5 (8.8), 5-HT6 ( 9.6), adernoceptors with the binding affinity of 8.9 for ?1, ?2A, ?2C and 9.5 for ? 2B, for dopamine receptors the binding affinity is 8.9 for D1 and D2, 9.0 for D4 and 9.4 for D3, histamine receptors have 9.0 for H1 and 8.2 for H2. The binding efficacy of the asenapine is high compared with the risperidone and olanzapine. Another major difference between asenapine and other antipsychotic drugs is that it exhibits little muscarinic receptor antagonist effects. An observational study is carried out to test the safety of the drug in adults. The adult patients with bipolar disorder are considered for the study. (Shahid et al., 2009). The patients must be confirmed with DSM-IV criteria, and must be aged between 18 – 70. The treatment used currently must have only very little effect on the disease. The exclusion criteria’s for this hypothesis are, history of intolerance of asenapine, presence of dementia, unstable medical illness, high risk for suicide, greater mental stress and history of stroke. (Pompili et al., 2011) So far 51 completed trials of which 29 are clinical pharmacology studies. These studies have concluded that asenapine is well tolerated in the patients with less adverse effects and extrapyramidal symptoms are less for both short term and long term. Weight gain was the notable clinical symptoms in the completed trials. Some of the notable side effects of asenapine are nausea, dizziness, akathisia, somnolence and oral hypoesthesia. Asenapine was administered sublingually in some studies. So based on these previous studies and findings, we can use asenapine for the treatment of bipolar disorder. The patients will be given asenapine drug for 12 weeks as an open study with drug concentration of 5 mg/ day. The dose concentration can be managed up to 20 mg/ day. Asenapine can be administered in pill form. Sublingual route is preferred for those who have difficulty in swallowing. Food and drink must be avoided 10 minutes before and after administration of the drug. The main advantage of sublingual administration is that the adsorption is very rapid and the drug enters the blood circulation in 0.5 – 1.5 hours with moderate bioavailability. (Pompili et al., 2011). The other studies have concluded that the activity of the drug is well tolerated by the patients. The clearance of the asenapine is of 4.6 mg at the rate of 1.5 mg/ kg. (Shahid et al., 2009). References: Barrett TB, Emberton, JE, Nievergelt, CM, Liang, SG, Hauger, RL, Eskin, E, Schork, NJ, Kelsoe, JR. (2007). Further evidence for association of GRK3 to bipolar disorder suggests a second disease mutation, Psychiatric genetics, 17 (6); 315 – 322. Barett, TB., Zhou, X and Kelsoe, JR. (2008). Promoter Variant in the GRK3 Gene Associated with Bipolar Disorder Alters Gene Expression, Biological psychiatry, 64 (2): 104 -110. Bensimon, G., Lacomblez, L and Meininger, V. (1994). A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis, The New England Journal of medicine, 330: 585 – 591. Manji, HK. (2010). Behavioral Neurobiology of Bipolar Disorder and Its Treatment, Springer. Noga, JT., Vladar, K and Torrey, EF. (2001). A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder, Psychiatry research, 106 (1): 25-34. Peacock, J. (2000). Bipolar disorder. Capstone Press. Pompili, M., Venturini, P., Innamorati, M., Serafini, G., Telesfro, L., Lester, D, Tatarelli, R., and Girardi, P. (2011). The role of asenapine in the treatment of manic or mixed states associated with bipolar I disorder, Neuropsychiatric Disease and Treatment, Vol. 7, pp: 259–265. Rowland, LP., Pedley, TA and Merritt, HH. (2009). Merritt’s Neurology. Lippincott Willaims and Walkins. Ucsdnews.ucsd.edu. (2003). UCSD Researchers Identify Gene Involved In Bipolar Disorder. Retrieved from: http://ucsdnews.ucsd.edu/newsrel/health/Mol%20Psy%20GRK3.htm Shahid, M., Walker, GB., Zorn, SH and Wong EH. (2009). Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. Journal of psychopharmacology, 23 (1): 65- 73. Read More