Effects of zinc sulfate on schizophrenia symptoms in patients undergoing atypical antipsychotic pharmacotherapy

ABSTRACT

Introduction:

It has been noticed that inadequate levels of zinc (Zn) can have adverse effects on the nervous system, which in turn leads to cognitive disorders. The present study was conducted to determine the effects of Zn sulfate on eliminating the symptoms of schizophrenia.

Methodology:

This study was a double-blind intervention study conducted in 2020. PANSS and HAM-D questionnaires as well as demographic information were completed for the participants. The patients were assigned to two groups with an equal number of 44 (n = 44). Zinc sulfate 220 mg capsules were delivered to the patients every 8 hours, and the control group received the placebo. Finally, the data of both groups were entered into the software and compared with one another.

Results:

No significant differences were found among the 88 participants regarding variables of age (P = 0.607), gender (P = 0.792), job (P = 0.596), income (P = 0.293), length of the illness (P = 0.965), and education (P = 0.281). Positive symptoms (P = 0.426), negative symptoms (P = 0.891), and psychopathologic symptoms (P = 0.100) had no significant statistical difference between the two groups before the intervention. However, within the second week, positive symptoms had significant differences between the groups (P = 0.029), and they were significantly lower in the experimental group. The fourth week following the therapy was associated with significant differences in positive (P = 0.005), negative (P = 0.036), and psychopathological (P = 0.002) symptoms in both groups. Moreover, within the sixth week, significant differences in positive (P = 0.007), negative (P = 0.002), and psychopathological (P = 0.008) symptoms were found between both groups, which were significantly lower in the experimental group.

Conclusions:

According to the observations made in this study, zinc sulfate improved symptoms of schizophrenia in the patients.

Introduction

Schizophrenia is among the most common psychological disorders involving about 1% of the world’s population without any identifiable cause even after half a century.[1] This illness is one of the ten major reasons for disability (incapability) in the world that can decrease life expectancy by 20%.[2] Around 50% of beds in psychiatric hospitals are occupied by these patients and high costs are spent for them.[1] Generally, according to DMS-5, diagnosis of schizophrenia requires at least two of the following symptoms for 1 month: delusion, hallucination, disorganized speech, abnormal motor behavior, and negative symptoms. In addition, subliminal symptoms or lasting symptoms for at least 6 months with considerably lower social or job performance.[3] Numerous studies have reported the intervening role of neurotransmitters in schizophrenia alone or in interaction with each other. Some neurotransmitters have been said to affect this disorder, for example, dopamine, glutamate, GABA, and acetylcholine.[4] With the patients’ immediate need for hospital care, continuous clinical care, rehabilitation, and supportive service, this illness must be seriously cured. The common pharmacotherapy for psychotic symptoms of schizophrenia includes antipsychotic drugs. According to studies, about 70% of schizophrenic patients who receive antipsychotic drugs show relative or primary improvement, whereas only 25% of them are completely cured.[5-8]

Recent studies have demonstrated the unbelievable positive effects of copper (Cu) and zinc (Zn) on brain health.[9] Following calcium (Ca), Zn is the second most abundant cation in the human body that is the major part of thousands of enzymes and proteins.[10]

Zn is a micronutrient required for the normal function of the human body, especially the brain and neural structure.[11-17] Lack of Zn deficiency would result in declined immunological function, tissue loss, pains in the digestive system, and sensory disorders. Lack of Zn would also involve the neural system and reduce learning abilities by changing the structure of behavior and cognition.[9,18] Zinc is found in different areas of the central nervous system including the cortex and amygdala; however, higher levels of this ion are found in neurons of the hippocampus.[19,20] There are several studies on the effects of Zn on schizophrenic patients, one of which has reported a lower Zn level in schizophrenic patients compared to healthy people. Moreover, they warn about the serum level of Zn as a risk factor. Kimura et al.[21] observed patients with schizophrenia had lower levels of Zn. Their research showed that glycolysis and many other enzymes in brain tissue need Zn to continue their operations. Baj found that there is no relationship regarding the levels of rare serum elements among schizophrenic patients. Therefore, it cannot be considered a predictive or diagnostic indicator of schizophrenia. Another study found that consuming supplementary Zn has an important role in preventing LBW (low birth weight) and improving growth and development in children.[22,23] In a study, Sharma et al.[24] reported that the level of Cu and Zn in patients with schizophrenia was significantly lower than the control participants and it suggested that the level of Zn and Cu in plasma might be a warning factor for this illness. There is a limited number of studies on this issue, so the present study aimed at evaluating the effects of zinc element in sulfate form on declining symptoms and decreasing treatment costs for that.

Material and Methods

Participants

The present study was conducted in the form of a double-blind clinical trial in 2020. It was admitted by the code of conduct from Jondi Shapoor University, Ahwaz, Iran, and registered at IRCT. The participants consisted of all 18–60-year-old schizophrenic patients of Golestan Hospital in Ahwaz who were selected based on DSM-5 criteria, inclusion and exclusion criteria, and based on psychotherapists who were faculty members too, regardless of their gender. According to the previous studies, the sample size was 44 (n = 44) in both experiment and control groups considering an error level of 5% and potentially 10% exclusion using the following formula. In total, 88 schizophrenic patients of the psychiatric ward at Golestan Mental Hospital of Ahwaz in 2020.

α = 0/05 ⟶ z₁ - a/2-1/96

B - 0/2z₁ ⟶ -B-0/85

Instrument

Aimed to collect data, PANSS, demographic, HAM-D, and side effect questionnaires were used. The HAM-D questionnaire (Hamilton Depression Rating scale) with 24 items aims to investigate depression; due to the likely exclusion of depressed patients from this study, the questionnaire needed to be completed by all participants, and only the patients with scores lower than 7 are included. The researcher-made demographic questionnaire consisted of patients’ information including age, gender, education, income, marital status, and length of illness. The PANSS questionnaire (positive and negative symptoms and psychopathology scale) with 30 items assesses the severity of schizophrenia, and it was completed for the participant at the start of the study and the following 2^nd, 4^th, and 6^th weeks to determine how effective Zn supplements were on improving schizophrenic symptoms in the patients.

The questionnaire of side effects of drugs including items of akathisia, skin rash, dehydration, and digestive effects was also completed for the patients with side effects of Zn sulfate.

Methodology

Patients were divided into two groups of 44. The intervention (experiment) group received zinc sulfate 220 mg capsules every 8 hours a day and the placebo was delivered to the control group. Both of the groups were simultaneously undergoing therapies including atypical antipsychotic drugs (risperidone and olanzapine) with an identical dose for 6 weeks. To randomize based on block randomization, the individuals were assigned to two distinct groups. Blinding was considered for this study. In addition, zinc sulfate capsules were similar to the placebo in form, color, flavor, and scent. The drug was delivered to the patients for 6 weeks. After that, PANSS and side effect questionnaires were completed in weeks 2, 4, and 6. The administrator of the project collected the data evaluated the patients and completed the forms with the help of an assistant. The subjects could leave the study any time they were to start receiving mood stabilizers, atypical antipsychotic drugs, and ECT (electroshock).

Statistical analysis

To analyze the data, descriptive statics methods were employed including frequency, mean percent, standard deviation, and maximum and minimum scores; to review the literature, inferential statistics including a multivariable covariance analysis test was used. In addition, SPSS23 was incorporated to analyze the data. The probability level to test the hypothesis of the study was <0.05.

Results

In the present study, 88 schizophrenic patients under pharmacotherapy with atypical antipsychotics who were hospitalized in Golestan Hospital of Ahwaz, Iran, were randomly assigned to two experiment and control groups. The demographic data of the patients are presented in Table 1.

Table 1.

Comparison of demographic data of the groups

Variables	Group		P
	Intervention	Control
Gender			0.792
Male	36 (81.81)	34 (77.27)
Female	8 (18.18)	10 (22.72)
Age	8 (18.18)		0.607
18-30	10 (22.7)	12 (31.8)
30-45	20 (59.1)	17 (50.0)
45-60	14 (18.2)	15 (18.2)
Job			0.596
Working	9 (20.5)	11( 25)
Unemployed	28 (63.6)	29 (65.9)
Retired	7 (15.9)	4 (9.1)
Income (million/month)			0.293
Below 2	23 (52.3)	25 (56.8)
2-4	20 (45.5)	15 (34.1)
Above 2	1 (2.3)	4 (9.1)
Length of the illness (year)			0.965
<1	8 (18.2)	8 (18.2)
1-5	17 (38.6)	16 (36.4)
5-10	14 (31.8)	16 (36.4)
>1	5 (11.4)	4 (9.1)
Education			0.281
Middle school	12 (27.3)	19 (43.2)
High school and college	23 (52.3)	17 (38.6)
Bachelor’s degree	9 (20.5)	8 (18.2)
Master’s degree and above	0	0

According to the results, there was no significant difference between the two groups in the evaluated parameters including age (P = 0.607), gender (P = 0.792), job status (P = 0.596), income (P = 0.293), length of the illness (P = 0.965), and education (P = 0.281). The mean of PANSS scores in both groups is sown for weeks 0 (pre-intervention), 2, 4, and 6 is shown in Table 2. As seen in Table 2, positive, negative, and psychopathological symptoms had no significant difference in week 0 and week 2. However, positive (P = 0.005), negative (P = 0.036), and psychopathological (P = 0.022) symptoms had significant differences in week 4 and this was significantly lower in the experiment group. Moreover, positive (P = 0.007), negative (P = 0.002), and psychopathological (P = 0.008) symptoms had significant differences in week 6 and this was significantly lower in the experiment group. Thus, zinc can decline various symptoms in schizophrenic patients in the 6^th week from the beginning of the intervention. Interestingly, during the present study, only 2 patients showed mild comorbid digestive symptoms from zinc sulfate. One of them had pain and sores in the stomach that was resolved after examination and special drugs taken with meals. The second case had diarrhea who got better after 1 day without any dehydration or other symptoms.

Table 2.

Comparison of PANSS scores in intervention and control groups in weeks 0, 2, 4, and 6

PANSS	Group		P
	Intervention	Control
Before the therapy (week 0)
Positive symptoms	4.80±20.40	4.50±21.20	0.426
Negative symptoms	5.82±28.09	4.98±28.25	0.891
Psychopathology	6.40±59.97	6.80±57.63	0.100
Week 2
Positive symptoms	3.84±18.63	4.20±20.54	0.029
Negative symptoms	5.23±25.59	4.64±26.95	0.200
Psychopathology	5.54±58.15	6.59±56.29	0.155
Week 4
Positive symptoms	3.38±18.04	4.02±20.31	0.005
Negative symptoms	4.65±24.61	4.45±26.68	0.036
Psychopathology	4.45±52.95	6.03±55.61	0.022
Week 6
Positive symptoms	3.03±17.56	3.58±19.84	0.007
Negative symptoms	4.20±23.70	4.17±26.18	0.002
Psychopathology	3.69±51.75	5.64±54.52	0.008

Discussion

Schizophrenia is a chronic mental disease that involves human thought, emotion, and behavior and it disturbs reality monitoring in patients.[1] Efforts to find effective treatments for this disorder are noticeable.[6] A limited number of studies have evaluated the effectiveness of interventions on schizophrenic patients. The present study aimed to investigate the effects of zinc supplements on schizophrenic patients. Here, it was observed that, before the intervention, the positive, negative, and psychopathological symptoms had no significant differences. After 2 weeks upon the start of the intervention, negative and psychopathological symptoms had no significant difference; however, positive symptoms showed significant differences, which were much lower in the intervention group. After 4 weeks, there was a significant difference among positive, negative, and psychopathological symptoms in both groups. Moreover, in week 6, there was a significant difference among positive, negative, and psychopathological symptoms in both groups which was much lower in the intervention group. Positive, negative, and psychopathological symptoms declined in the intervention group in weeks 4 and 6 compared to the control group, and this decline was statistically significant.

Mortazavi et al.[25] investigated the effectiveness of zinc (Zn) element on schizophrenic patients under therapy with risperidone. The results of their study showed that Zn might be an influential factor in the management of schizophrenic patients. Consistent with Mortazavi et al., in the present study, PANSS scores in the intervention (experiment) group were much lower compared to the control group and this decline began from week 2, it was observable in week 4 for Mortazavi et al., though.[25] In both studies, no major comorbid problem from zinc sulfate was observed in the patients. Unlike Mortazavi et al., at the beginning of the present study, PANSS and HAM-D were completed for all patients; according to HAM-D, patients with lower scores than 7 were excluded from the study for being prone to comorbid depression. Because previous studies (e.g. Nazarinasab et al.[26] ) reported that Zn could improve depression symptoms added to pharmacotherapy, and in the present study, unlike Mortazavi et al., disturbing factors related to depression were omitted through HAM-D, and patients with comorbid depression were excluded; improvement of negative factors was specifically related to schizophrenic symptoms, with no relationship with improved mood or depression; and this is one of the strengths of the study. In the present study, as well as in Mortazavi et al., schizophrenic patients were under treatment with atypical antipsychotic drugs.

Amani et al.[27] assessed the effectiveness of Zn on cognitive conditions and observed that levels of Zn in serum had positive relationships with IQ, memory, and concentration in female university students. The results of the present study were consistent with Bhatnagar[23] who investigated the effects of Zn on growth and development, and in both studies, Zn improved memory and learning. Although in the present study, like some previous studies, the primary level of Zn has not been evaluated, the observed results of Kimura,[21] Bhatnagar,[23] Walwork,[28] Sharma,[24] and Tokdemir[29] indicated that schizophrenic patients showed lower levels of Zn compared to the control group; however, these results were inconsistent in some cases with Holcomb[30] who did not admit any effects of Zn, and no difference was observed between the groups. All ordinary antipsychotic drugs influence dopamine D2 receptors and cause psychotic symptoms. However, antagonists of D1 receptors may decline the N-Methyl-D-Aspartat receptor’s activity, leading to decreased hyperactivity of glutamatergic. Strong D2 antagonists may have the least influence on balancing glutamatergic activity.[31] According to this, and based on the mechanism mentioned, the present study reported that Zn might decrease positive, negative, and psychopathologic symptoms in schizophrenic patients, and Zn supplements could improve these patients’ conditions regardless of the lack or abundance of Zn.

Conclusion

The findings of the present study showed that Zn sulfate improved symptoms of schizophrenic patients, so these symptoms were significantly lower in the intervention group. Moreover, the observed side effects of Zn sulfate. As a result, Zn sulfate is influential in improving symptoms in schizophrenic patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.