Open Trial of the Addition of Divalproex Sodium for Improving the Symptoms of Batak and Non-Batak Males with Schizophrenia in North Sumatra, Indonesia

Schizophrenia is a chronic mental disorder that includes a group of heterogeneous symptoms and cognitive disorders. Based on evidence from epidemiologic data, imaging and post-mortem analyses, A hypothesis on the development of nerves and dopamine which has transformed into two main theories of schizophrenia is obtained. Other hypotheses emphasize the effect of genetic and environmental factors during the early stage of life and the lack of brain development with negative effects on mental health in adulthood. Schizophrenia is generally marked by psychopathologic damage involving cognitive, emotional, perceptual, and behavioral aspects. The damage which manifests in patients and influences epidemiology is usually severe and long-lasting. Schizophrenia is a common psychotic disorder with the early-onset of age of 18 years old. It is a chronic disease that disturbs patients and their families and brings a big impact on the social and economic status of patients. For male patients, the attack peaks at the age of 10 - 25 years. About 90% of patients under treatment are at the age of 15 - 55 years (1-5).

The treatment of schizophrenia patients is suboptimal where chronic recurrence might happen and side effects of therapy are concerning. Monoamine, especially dopamine, has been the focal point in pathophysiology research of schizophrenia for several years. Evidence suggests abnormalities in neurotransmitter systems, including gamma aminobutyric acid ergic (GABAergic) system (5).

Antipsychotics are the gold standard for the treatment of patients with schizophrenia. However, not all patients respond well to antipsychotic monotherapy. A recent pharmacoepidemiologic study evaluated the psychotropics prescription and found the substantial effect of mood stabilizers as adjunctives. About 15% to 50% of patients in various countries show improvements over time by adding mood stablizers on antipsychotic drug Divalproex sodium is a moodstablizes that has been used with antipsychotics as an adjunct therapy. The dosage and duration of adding this medication should be adjusted (6).

The variability in medication response depends on extrinsic factors, such as food and additional prescription, and intrinsic factors, such as gender, ethnicity, age, weight, liver and kidney function, and genetic differences in enzymes metabolizing or carrying the drug. Genetic variety can affect metabolizing enzymes. Several polymorphisms can influence the selectivity of substrate or inducibility of drug metabolic pathway. Genetics is a factor affecting drug effects by changing pharmacokinetic or pharmacodynamic properties. Besides, environmental and cultural factors related to diet, climate, and habits, psychosocial factors, and beliefs towards ethnic groups will influence medicine absorption. The difference in distribution, biotransformation, excretion, and receptor interaction will influence the effectiveness or obedience towards the discipline in medicinal therapy (7-9).

In general, ethnic groups of the Indonesian population are determined to follow a paternalistic line (father/male), for example, the Batak and Javanese tribes. In this case, Batak tribe men will give offspring who are also Batak. The Batak tribe is one of the Indonesian ethnic groups located in North Sumatra. The Batak name is a collective theme to identify several ethnic groups who live and come from Tapanuli and East Sumatra. Not only the Batak tribe but also some other tribes such as Java, Malay, and Minang are the inhabitants of the Sumatra region, especially North Sumatra (10).

With the effect of ethnic factors on the variability and absorption process of the drug, this study tried to provide an overview of the differences between Batak and non-Batak tribes towards the addition of divalproex sodium as one of the additional therapies to one of the typical antipsychotics, namely risperidone, to reduce symptoms in the treatment of schizophrenia.

This study aimed to determine the differences in positive and negative syndrome scale (PANSS) scores between Batak and non-Batak males with schizophrenia receiving risperidone treatment alone or combined with divalproex sodium.

Table 1 shows the characteristics of study subjects in the Batak and non-Batak tribes. There was no significant difference between the ethnic groups in terms of patients’ characteristics and PANSS scores at baseline. Therefore, the groups were homogeneous before the intervention.

Table 2 shows the difference in the PANSS positive subscale scores between the groups receiving risperidone monotherapy or combined with divalproex sodium. In the Batak tribe, there was a significant improvement in the PANSS positive score from the beginning of the study (week 0) to the end of the study (week 6) between those receiving additional divalproex sodium therapy (15.400 ± 1.352) and those who only received risperidone therapy (19.733 ± 1.486), (P = 0.000 and P < 0.001, respectively). The same results were found for the non-Batak ethnic group, that is the group receiving additional divalproex sodium showed more improvement at the end of the study (14.820 ± 1.355) than those who only received risperidone therapy (18.933 ± 1.458) (P = 0.000 and P < 0.001, respectively). However, the differences between the two Batak and non-Batak tribes were not significant in the improvement of the PANSS positive subscale scores for each therapy at the end of the study at week 6 (P = 0.766 and P > 0.05, respectively).

Table 3 shows that in the Batak tribe, there was a significant difference in the improvement of the PANSS negative subscale scores from the beginning of the study (week 0) to the end of the study (week 6) between those receiving additional divalproex sodium therapy (8.867 ± 1.060) and those who only received risperidone therapy (12.200 ± 2.932) (P < 0.001). For the non-Batak ethnic group, there was a significant difference at the end of week 6 between patients that received additional divalproex sodium (8.867 ± 1.060) and those who only received risperidone therapy (12.200 ± 2.932), (P = 0.000 and P < 0.001, respectively). There were no significant differences in the improvement of the PANSS negative subscale scores for each therapy at the end of the study (week 6) between the Batak and non-Batak tribes (P = 0.789 and P > 0.05, respectively).

As shown in Table 4 for the Batak group, the difference was significant in the improvement of the PANSS total score from the beginning of the study (week 0) to the end of the study (week 6) between patients receiving additional divalproex sodium therapy (46.067 ± 2.404) and those who only received risperidone therapy (55.200 ± 1.740) (P = 0.000 and P < 0,001, respectively). For the non-Batak ethnic group, there was a significant difference at the end of week 6 between patients received additional divalproex sodium (45.201 ± 2.186) and those who only received risperidone therapy (54.600 ± 1.156) (P = 0.000 and P < 0.001, respectively). There were no significant differences in the improvement of the PANSS total scores for each therapy at the end of the study (week 6) between the Batak and non-Batak tribes (p = 0.673 and P > 0.05, respectively).

Based on Table 5, there were no significant differences in side effects in each group between patients receiving additional divalproex sodium or risperidone monotherapy (P > 0.05).

This is the first study conducted in Indonesia and North Sumatra (one of the provinces of Indonesia) to investigate differences in drug response and symptom severity measured through PANSS scores in two different tribes, i.e. the Batak and non-Batak tribes. The Batak tribe is the dominant tribe among other tribes in North Sumatra based on data from the Central Bureau of Statistics in North Sumatra (16). Therefore, this study tried to explore different drug responses as a function of different characteristics possessed by each ethnic group, including Batak and non-Batak as the main ethnic groups in North Sumatra.

Based on Tables 2 - 4, this study showed the benefits of adding divalproex sodium to the treatment of schizophrenia to reduce symptoms, especially positive symptoms, measured by the PANSS in Batak and non-Batak tribes for six weeks. This can be related to dopamine hyperactivity that is considered as one of the main reasons for positive symptoms in schizophrenia. It is known that GABAergic drugs such as valproate are potent for the treatment of schizophrenia because they have a working principle that decreases dopamine regulation. Adequate loss of glutamate function in GABA interneurons containing parvalbumin in the hippocampus can cause hyperactive glutamate output from glutamate neurons projected by this circuit to mesolimbic dopamine. In other words, if the NMDA (N-Methyl-D-Aspartate) receptor in the hippocampal ventricular GABA interneuron is hypoactive, the glutamatergic pathway to the nucleus accumbens will be too active, which stimulates GABAergic neurons projected to the globus pallidus to disrupt the ventral tegmental area (VTA), which in turn inhibits the GABA release from globus pallidus to VTA. This will lead to the disinhibition of the dopamine pathway in the mesolimbic area and thus the excessive release of dopamine in the nucleus accumbens. In addition, glutamate and GABA, through local and integrative circuit control and feedback, regulate cortical and subcortical activation and can be associated with the expression of psychotic symptoms, mood deficiency, cognitive function, and attention and social interaction (17-19).

In addition to affecting the metabolism of coadministered antipsychotics, valproate can modify clinical symptoms in schizophrenia through epigenetic modification. Recent research in schizophrenia shows the deficit of GABAergic neurotransmission Functions detected in schizophrenic patients are related to the downregulation of several GABAergic genes, including glutamate acid decarboxylase 67 (GAD67) and reelin. This downregulation can be a pathogenetic mechanism that underlies complex symptomatology in schizophrenia. This includes positive, negative, and cognitive symptoms.

Therefore, in terms of pharmacological intervention that normalizes GABAergic neurotransmission (such as adjunctive valproate) appears as a new target in strategies for treating schizophrenia. This is while antipsychotic drugs currently in use are not designed to target GABAergic transmission (4, 20-22).

Several previous studies, such as those conducted by Abad N et al. (23), Citrome et al., (24) and Casey et al. (25), have shown many effects for adding divalproex sodium to several types of antipsychotics such as risperidone, olanzapine, and haloperidol for schizophrenia treatment. This strategy is also beneficial for changes in the PANSS score, hostility PANSS, in terms of both positive symptoms, agitation and aggression, and negative symptoms. Although the method is different in each study, the objective is the same, which is benefiting from adding divalproex sodium for the treatment of schizophrenia. The duration of adding divalproex sodium for schizophrenia treatment is also different. Some research has argued that treatment was only seen as significant from the beginning of the administration to the second, third, and fourth weeks, while there are also studies reporting the benefits until the 12th week with no significant change thereafter (23-28). Other studies showed no significant improvement at the end of the study and more benefits were seen at the beginning of the addition of divalproex sodium especially for the improvement of positive symptoms when compared to those who were not treated with Divalproex sodium (29).

Valproate was also reported to be useful for patients with treatment-resistant and chronic schizophrenia. In addition, the combination of divalproex sodium with antipsychotics can accelerate the treatment period compared to monotherapy with antipsychotics (30, 31). This is in line with this study showing that divalproex sodium addition was effective from week 3 to week 6 of the study. This could be the basis for seeing the benefits of divalproex sodium addition for the treatment of schizophrenia.

A similar study was carried out by Tarigan and Syamsir in North Sumatra with 92 people with schizophrenia who were divided into two groups. By looking at the BPRS scores for weeks 1 and 9 after the use of haloperidol antipsychotics and the addition of divalproex sodium, the difference between the scores was significant at P = 0.001 (32). The difference of the study was only in use of the combination of a first-generation antipsychotic (haloperidol) with divalproex sodium regardless of differences in tribes of North Sumatra. However, in this study, the effects of the addition of divalproex sodium on the treatment of schizophrenia were compared between Batak and non-Batak people. This is based on that the Batak tribe is famous for its openness, spontaneity, and aggressiveness both physically and verbally, rudeness, and stubbornness. Moreover, the Batak people often choose to express their anger. The Batak people who prioritize self-esteem tend to focus on themselves, their families, or relatives around them. If there are strangers who interfere or do bad things, the Batak people will tend to directly attack with emotion. This makes the Batak tribe possess weak emotional regulation. This is while non-Batak tribes are not too expressive and are able to control their anger with better emotion regulation. This affects the way of socialization of the Batak tribe to be less adaptive, which results in their poor regulatory ability compared to non-Batak tribes (33-35).

A recent review of drug metabolism shows that one of the most important sources of variability in drug response is genetic variability in drug metabolic enzymes. Differences between ethnic groups in the metabolizing enzymes have the potential to cause variability in dose choice. Cytochrome or cytochromes P450 (CYP) is the main source of variability in pharmacokinetics and drug response. The expression of each CYP is influenced by a combination of mechanisms and unique factors including genetic polymorphism, induction by xenobiotics, regulation by cytokines, hormones, illness duration, sex, and age. Gene allele polymorphism is very dependent on ethnicity and leads to different pharmacogenetic phenotypes (7-9).

No significant differences were seen in symptom reduction between people with schizophrenia from the Batak and non-Batak tribes as measured by the PANSS, which can be due to various factors derived from extrinsic factors such as the environment (diet, climate, alcohol, drugs, and pollutants) although they were not explored further in this study. These factors can surely lead to variations in the broad drug response in individuals and even wide variations in individual groups. Cultural or psychosocial factors such as ethnic groups, attitudes, and beliefs may influence the effectiveness or adherence to a drug therapy discipline. It is known in cultural psychiatry that cultural interactions and psychiatric disorders have roles to play in differences in symptoms, diagnosis, and variations in dose response to psychotropics among different ethnic groups. Further research related to gene polymorphisms and socio-cultural influences may be fruitful in the future to see drug responses in certain ethnic groups (9).

The metabolic effects of the combination of valproate with typical and atypical antipsychotics include weight gain, sedating effects, and the increasing liver enzymes and gastrointestinal side effects. In this study, the side effects of divalproex sodium such as weight gain and gastrointestinal and liver dysfunction were not measured. Some medical interaction has been reported between valproate and antipsychotics, but there is much evidence showing that valproate might increase the effect of atypical antipsychotics in treating schizophrenia (36-38).