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Plasma homocysteine in first-episode schizophrenia: 1-year outcome, a prospective study

El Sayed El Taweel, Mohameda; ElShafie, Taghreed, M.b; Heba, K.c

Middle East Current Psychiatry: April 2018 - Volume 25 - Issue 2 - p 42–49
doi: 10.1097/01.XME.0000526695.73173
Original Articles

Background Accumulating evidence indicates that altered one-carbon metabolism occurs in schizophrenia. Plasma total homocysteine (Hcy) is attracting increased attention. Elevated plasma Hcy levels have been proposed as a potential hey substance in schizophrenia.

Objectives This study was carried out to confirm the results of previous research on schizophrenia that reported high serum Hcy levels and to test the impact of increased plasma Hcy levels on the symptom profile in first-episode schizophrenic male patients at index hospitalization. Other aims included investigating baseline Hcy level as a potential marker predicting schizophrenia outcome 1 year following index hospitalization.

Patients and methods The study prospectively investigated a group of 50 male patients with first-episode schizophrenia. These patients were compared with 50 apparently healthy male participants, matched for age, sex, and ethnicity, who served as controls. The diagnosis was made according to the ICD-10 Diagnostic Criteria for Research through conducting Mini International Neuropsychiatric Interview. Anthropometric indices and biochemical parameters including plasma Hcy levels were determined using a standard procedure. The patient group was divided into a patient group with high serum Hcy levels and a patient group with normal serum Hcy levels. Both patient groups were compared at baseline and at 1 year for demographic, clinical, and treatment characteristics.

Results Male patients diagnosed with first-episode schizophrenia have significantly higher plasma Hcy levels more sel than healthy controls. The percentages of schizophrenic patients with high Hcy levels were 40%, whereas 60% showed normal plasma Hcy levels. The patient group with increased plasma Hcy levels presented with significantly increased severity of psychopathology and treatment characteristics at index hospitalization compared with those with normal serum Hcy levels. Multiple regression analysis showed that altered plasma Hcy levels are associated with more severe psychopathology and less favorable outcome in a 1-year follow-up study.

Conclusion We found higher rates of Hcy in patients with first-episode schizophrenia compared with matched controls. Our results suggest that Hcy might play a role in the pathogenesis of schizophrenia and may negatively influence outcome in terms of symptom severity and treatment characteristics; future studies are required to examine this association further. In the meantime, there is a need for more widespread testing of Hcy levels in first-episode schizophrenia and for the development of appropriate management strategies.

aDepartment of Psychiatry and Addiction Medicine Hospital, Cairo University Hospital

bPsychiatry Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

cDepartment of Clinical and Chemical Pathology, Ministry of Health Pathology, Kawit, Philippines

Correspondence to Taghreed M. ElShafie, MD, Al-Azhar University, 34 Ahmed mostaffa street Alnozha Algadeda, Cairo 1234, Egypt Tel: +20 202 621 2306/+20 202 624 9514; e-mail:

Received March 5, 2016

Accepted October 9, 2017

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Schizophrenia is a devastating psychiatric disorder 1. The onset of the disorder typically occurs in late adolescence or early adulthood and includes positive, negative, affective, and cognitive symptoms 2. Schizophrenia is a chronic syndrome of unknown etiology; whereas around 3% of the general population suffers a first episode of psychosis during their life, schizophrenia affects ~1% of the population worldwide 3.

Schizophrenia is a challenging complex disease that is encountered in modern psychiatry. Unfortunately, the outcomes of schizophrenia are unfavorable as very few treatments are effective for all dimensions of the illness.

Existing studies suggest that despite revolutionary advances, good clinical outcome (for example, improvement in symptoms) of schizophrenia remains limited, whereas considerably fewer patients improve in social functions (e.g. employment, independent living) 4,5.

After a century of scientific effort to better understand the nature of the disorder, there is still no clear control of the symptoms and there is a need to change the strategies followed to understand the pathophysiology of the disorder and the possible therapeutic targets for new drugs 6,7. The multifaceted nature and heterogenous cause of schizophrenia could explain this difficulty 8.

A substantial body of literature confirms that one-carbon metabolism alterations are frequently reported among first-episode schizophrenic patients 9–13. Homocysteine (Hcy) is a nonprotein neurotoxic amino acid that has been proposed to be an independent risk factor for schizophrenia through developmental effects on brain structure and function 14. There is evidence that increased Hcy level is associated with higher schizophrenia risk as reported by two meta-analysis studies 15,16. Some investigators reported that one-carbon dysregulation in terms of elevated Hcy levels also occurs in siblings of schizophrenic patients 17. In addition, some investigators found that schizophrenic patients with a positive family history of schizophrenia show significantly higher Hcy and lower vitamin B12 levels compared with those without positive first-degree relatives with schizophrenia 9. These findings suggest that a genetic factor may contribute toward the link between one-carbon metabolism and schizophrenia 15,16. Several studies have shown that Hcy levels may be correlated positively with the duration of untreated psychosis 11, the severity of negative symptoms 18–20, and cognitive deficits 21.

The exact mechanism remains unclear; it has been asserted that DNA damage inflicted by Hcy induces apoptosis 22,23 triggers mitochondrial dysfunction 24 and promotes oxidative stress 25. However, it seems that the interactions between Hcy and N-Methyl-D-aspartic acid receptors seem to be the most relevant to schizophrenia pathophysiology 26.

On the basis of this background, we hypothesize that one-carbon metabolism may be disrupted in first-episode psychotropic drug-naive male schizophrenic patients and this dysregulation may have an impact not only on the index hospitalization profile but also a deleterious effect on psychopathology in a 1-year follow-up.

Limitations of previous studies included a limited sample size and heterogeneity in selection. At the same time, in developing countries, there were little if any studies on the outcome of patients with altered one-carbon metabolism. Moreover, there are no data to indicate whether the outcome of first-episode schizophrenic patients with elevated plasma total Hcy levels was the same or different compared with patients with normal plasma Hcy levels.

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This study aimed to explore whether there is a difference between plasma total Hcy level of first-episode schizophrenic patients at index hospitalization and those of healthy control participants.

  • To compare baseline plasma Hcy among schizophrenic patients and to test whether this difference has an impact on symptoms profile at index hospitalization.
  • To test whether an increased plasma Hcy at index hospitalization could be a predictor for outcome in a 1-year follow-up. If meaningful data can be obtained from this study, we can suggest that patients with high homocyste may need dietary supplementation treatment.
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Patients and methods


The study case–control cross sectional study was carried out on a convenient sample of first-episode schizophrenic patients. This study was carried out in the period between March 2009 and September 2011.

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The study was carried out at Kuwait Mental Health Center after it received approval from the Local Scientific and Ethical Committee.


Before any procedure was performed, the study protocol was approved by the Local Research and the Ethics Committee.

Participants and/or relatives were informed about the study protocol. After they agreed to participate, they voluntarily expressed in a written informed consent document their desire to participate in the research.

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Fifty first-episode schizophrenic psychotropic drug-naive male inpatients and fifty healthy comparison participants were studied. Healthy comparison participants were selected from among those individuals who underwent physical examination for employment. Healthy comparison participants were excluded if they had a history of physical, mental, genetic, substance use disorders, a family history of psychotic disorders or mood disorders, or a genetic illness among first-degree or second-degree relatives on the basis of a self-report. Both groups were matched for sex, age, BMI, smoking status, and coffee drinking using 1 : 1 matching. The patient group was recruited from among those admitted to the Kuwait Mental Health Center, Kuwait and were examined within 24 h since admission. The study was approved by the local ethical and scientific committee. The schizophrenic group was diagnosed through conducting a Mini International Interview (MINI) 27 using the ICD-10 Diagnostic Criteria for Research 28. The inclusion criteria were as follows: age between 21 and 30 years, no evidence of neurological deficits, negative urine screening for illicit drugs (cannabis, amphetamine, opiates, and ecstasy), no history of drug and/or alcohol use or abuse disorder during 1 year before the onset of psychotic symptoms and no hospitalization in the 6 months before the recruitment phase of the study, a reliable care provider, and stability of diagnosis during the follow-up period. After the recruitment, all patients and controls were screened for chronic physical illness (history of hypertension, diabetes, hyperlipidemia, peripheral vascular disease, coagulopathy, and the presence of hematological, renal, or hepatic disease). Because of the potential confounding effects on plasma levels of Hcy, participants who had evidence of chronic physical illness were excluded on the basis of consultation with an internal medicine specialist. Notably, none of the patients or controls were receiving anti-inflammatory medications or vitamin supplements on a regular basis. This screening procedure was performed before data collection. For the purpose of comparison, the patients were divided into two subgroups (on the basis of plasma total Hcy levels) at index hospitalization. The first subgroup included patients with elevated plasma total Hcy level.

The second subgroup included patients who had normal plasma Hcy levels. The two patient subgroups will be followed regularly and evaluated at scheduled visits (at least every 2 months) during a 1-year observational follow-up period after index hospitalization.

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Assessment tools

  • Baseline (initial) assessment for all participants (patients and healthy comparison participants) includes the following:
    • A detailed psychiatric interview including information on sociodemographic data. Dietary assessment was performed using the Food Frequency Questionnaire. The Food Frequency Questionnaire is an advanced form of a checklist in the dietary history method, and asks respondents how often and how much food they ate over a specific period 29. Presenting about 100–150 foods, this questionnaire takes 20–30 min to complete and can be self-administered or completed by an interview. This method enables the assessment of long-term dietary intakes in a relatively simple, cost-effective, and time-efficient manner.
    • Anthropometric assessment: The weight (in kg) was measured using a weighing scale. Height (in cm) was determined with the participants in a standing position without footwear using a measuring rod attached to a fixed scale. This measured to an accuracy of 0.1 cm. The BMI in kg/m2 was calculated using weight/height2.
    • Laboratory workup: In addition to routine laboratory testing [including serum levels of low-density lipoproteins, high-density lipoproteins, total cholesterol, triglycerides (glucose, creatinine), serum levels of total Hcy (tHcy), folate, and vitamin B12 level were assessed]. Plasma tHcy was measured using the enzyme immunoassay method. folate and vitamin B12 were analyzed using high-power liquid chromatography. Laboratory workup was performed within 2 days of recruitment and repeated every 6 months throughout the study. Blood samples were obtained between 7.30 and 8.30 a.m. after at least 10-h overnight fasting.
    • MINI 27: This interview was translated and validated into Arabic 27 using the International Classification of Mental disorders Research Criteria (ICD-10-RC) 28 to diagnose schizophrenia.
    • The severity of psychopathology (symptoms duration and severity and under lying causes) among patients was measured by the following:
      • Positive and Negative Syndrome Scale (PANSS): This scale was used to measure symptom severity 30. PANSS is a 30-item semistructured interview designed to assess three symptom categories associated with schizophrenia: positive symptoms, negative symptoms, and general symptoms. One trained and calibrated rater assigned a score from 1 to 7 for each item, with higher scores indicating more severe psychopathology. The range for the PANSS total score was from 30 to 210. The PANSS is a relatively brief interview, requiring 45–50 min to administer.
      • Montgomery–Asberg Depression Rating Scale 31: This scale is used to evaluate depressive symptoms.
      • GEOPTE Scale for the Subjective Perception of Cognitive Deficit 32: This scale provides a measurement of cognitive operations performed in social stimuli (social cognition) rather than neuropsychological functions. This consists of a self-report scale of 15 items. It is designed to evaluate subjective perception of cognitive deficits, the patient’s perception as well as that of his/her family members. Both versions of the scale (patient and caregiver) were applied.
      • Fagerström Test for Nicotine Dependence 33: This is the most widely used instrument to establish and quantify nicotine dependence, with six items that provide a total score ranging between 0 and 10. It was applied to all participants.
  • End point evaluation assessment at 1 year following index hospitalization (patients only). All patients were re-evaluated 1 year after index hospitalization by applying the same tools as those used at baseline assessment.
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Statistical analysis

Parametric v2 and t-tests were used to compare the patients and healthy comparison participants on demographic, clinical, and laboratory variables. Analyses of covariance were performed considering the plasma Hcy level as the dependent variable and group (patients vs. controls) as the independent variable, and controlled for age, serum folate, vitamin B12, and smoking as indicated. Patients were categorized into two groups: patients with normal Hcy and patients with elevated Hcy levels. Analyses of covariance adjusted by confounding variables were used to compare the two Hcy groups. Post-hoc analyses were carried out on all main effects (Bonferroni corrected P=0.05). The Statistical Package for Social Science, version 19 (SPSS Inc., Chicago, Illinois, USA), was used for statistical analyses.

All statistical tests were two tailed, and significance was determined at the 0.05 level.

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Out of 56 patients, only 50 completed the minimum duration and follow-up visits of the study.

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Diagnosis and dropout

All findings of diagnoses and dropout can be found in Table 1. Six patients of the original sample did not complete the study. Two patients were given different diagnoses during follow-up and four patients did not complete the minimum duration.

Table 1

Table 1

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Descriptive data of patients diagnosed with first episode schizophrenia and healthy comparison participants (at baseline).

  • Demographic and anthropometric characteristics showed no significant differences in any of the parameters when comparing patients with the corresponding healthy comparison participants’ values (P<0.05) (Table 1).
  • Laboratory characteristics. There was a significantly higher plasma tHcy [16.45 (8.13) vs. 11.98 (3.22)] (P<0.001) in patients compared with the corresponding control values. The plasma folate levels were significantly lower [5.01 (1.08) vs. (6.96 (4.62)] (P<0.03) in patients compared with the corresponding healthy comparison participants. However, there were significantly lower levels of plasma vitamin B12 [365.45 (221.98) vs. [485.85 (147.83)] (P<0.02) in patients compared with the corresponding healthy comparison participants. No significant differences were noted in the other parameters.
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Categorizing patients based on baseline plasma homocysteine levels

Baseline demographic, anthropometric, and clinical characteristics in patient subgroups. Patients with elevated plasma Hcy at index hospitalization had significantly more severe psychopathological manifestations in PANSS-negative symptoms [28.65 (7.65) vs. 21.71 (8.31), P<0.001] and in PANSS-general psychopathology [40.14 (9.76) vs. 32.95 (10.43), P<0.001]. In addition, depressive symptoms scores were significantly higher in patients with high plasma Hcy levels compared with those with normal Hcy levels [20.82 (9.54) vs. 17.73 (9.82), P<0.001]. Social cognition was significantly worse in patients with elevated Hcy levels compared with the other patient groups in both patient and caregiver versions (P<0.001). Patient with positive family history of schizophrenia (first-degree or second-degree relatives), being single, and employment were significantly higher in patients with high Hcy levels in comparison with those with normal Hcy levels (P<00001, <0.001, and <0001, respectively). No significant differences were noted in the other parameters, P<0.05 (Tables 2 and 3).

Table 2

Table 2

Table 3

Table 3

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End point assessment demographic, anthropometric, and clinical characteristics in patient subgroups

Patients with high plasma Hcy levels were more frequently single (60 vs. 15%, P<0.001), receiving social affairs benefit (15 vs. 4%, P<0.01), and less likely to be in paid employment. They were significantly heavier [69.64 (8.65) vs. 66.12 (9.23), P<0.001, increased BMI [28.32 (6.72) vs. 25.54 (9.78), P<0.0001] and had more frequent admissions. Furthermore, compared with patients with normal plasma Hcy levels, those with high Hcy levels had more severe psychopathology manifested by high scores in PANSS-negative symptoms [26.14 (8.32) vs. 14.13 (7.43), P<0.001], PANSS-general psychopathology [32.15 (9.41) vs. 24.15 (11.43), P<0.001], more severe depressive symptoms [19.11 (7.98) vs. 9.46 (6.32), P<0.0001], and more impairment in social cognition assessment in the patient-rated version [38.11 (9.87) vs. 29.16 (10.41), P<0.003] and the caregiver-rated version [41.32 (11.56) vs. 30.12 (9.86), P<0.004]. Higher antipsychotic dosage [chloropromazine equivalent; 458.26 (224.82) vs. 360.18 (230.19), P<0.002], polytherapy with antipsychotic (60 vs. 8%, P<0.001), and more frequent switches [3.69 (1.64) vs. 1.21 (0.65), P<0002] were significantly higher in those with high plasma Hcy levels than in patients with normal Hcy levels (Table 4). A P value refers to the comparison of mean ranks of patients assigned to the treatment with the respect to baseline plasma Hcy levels using the Mann–Whitney U-test, with the exception of sex and education distribution assessed using χ2-test and Fisher’s test significant differences (P<0.05). In terms of C-correlation between Hcy and some selected variables in the patient group), we found that high Hcy levels correlated positively with the severity of negative symptoms and general psychopathology assessed by PANSS (r=0.363, P=0.006 and r=0.349, P=0.008, respectively), severity of depressive symptoms (r=0.416, P=0.007), and poor social cognition, patient-rated version (r=0.408, P=0.006). Furthermore, higher baseline Hcy predicted longer duration of index hospitalization (r=0.375, P=0.003), higher antipsychotic dosage (r=0.349, P=0.006), more frequent admissions during a 1-year follow-up period (r=0.382, P=0.006) and antipsychotic polytherapy (r=0.471, P=0.008), and more antipsychotic switches (r=−0.309, P=0.003) (Table 5).

Table 4

Table 4

Table 5

Table 5

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The main results of this study are as follows: (i) First-episode schizophrenic patients are characterized by higher plasma Hcy and lower levels of folate and vitamin B12 compared with healthy control participants. These findings cannot be attributed to differences in age, BMI, or cigarette smoking in age as associated or causal factors. (ii) Patients with baseline high Hcy showed more severe psychopathological manifestations, more depressive symptoms, and a more deteriorating social cognitive performance than patients with normal Hcy levels. (iii) High Hcy levels at index hospitalization may predict a less favorable outcome over a 1-year follow-up period.

Our findings are in agreement with previous studies showing higher levels of Hcy and lower levels of folate or vitamin B12 in first-episode psychosis patients 10–12.

Studies measuring serum folate levels in patients with schizophrenia have consistently found significantly lower levels in those with the disorder compared with control participants 34–36. In addition, our results showed an association between a positive family history of schizophrenia and elevated plasma Hcy levels in first-episode schizophrenic patients. This is consistent with several studies that reported an association between a family history of schizophrenia and higher plasma Hcy levels 37–41. We also found that the first-episode schizophrenia patient group with high plasma Hcy levels had more severe psychopathological manifestations at index hospitalization as indicated by higher scores on PANSS scoring, more severe depressive symptoms, and poor social cognitive performance in comparison with those with normal plasma Hcy levels. These results are in line with previous studies showing that higher Hcy and lower folate levels are associated with higher severity of negative symptoms 18–20. In a randomized, double-blind, placebo-controlled, crossover design, patients with elevated Hcy levels were administered oral folic acid, B12, and pyridoxine for three adjunct treatments, and B vitamin appeared to be potentially useful in those with high Hcy levels 42. However, there are also studies that have failed to confirm this relationship 11,42–44. Inconsistent results might be because of recruitment of various subgroups of patients including first-episode schizophrenia-spectrum patients, acutely relapsed inpatients, or chronic patients.

We also found that during a 1-year period following index hospitalization, patients with baseline high Hcy levels showed little improvement in psychopathology than those with baseline normal Hcy.

Notably, we have also found that higher Hcy at index hospitalization may predict more severe psychopathology symptoms as assessed with the PANSS, higher depressive symptoms (using Montgomery–Asberg Depression Rating Scale), worse social cognition performance (using GEOPTE), longer duration of index hospital stay, more frequent admissions, antipsychotic polypharmacy and frequent switching strategies, and more deleterious impact over a 1-year follow-up period. These findings may indicate that baseline Hcy levels may be a marker for tailoring a treatment plan including nutritional intervention as an adjunctive treatment in first-episode patients. Some studies found that folate supplementation reduced Hcy levels in individuals with schizophrenia 42. This may help to avoid prescribing antipsychotic drugs at higher dosages and minimizing antipsychotic polypharmacy or multiple switching with hazardous consequences and unnecessary concomitant medications.

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The present study has several limitations that require further discussion and therefore our results should be interpreted with caution. First, it should be noted that our sample size was limited.

Furthermore, we did not measure methylmalonic acid levels, which would have enabled differentiation between impaired folate and vitamin B12 status; we also did not genotype the MTHFR polymorphisms that may alter the levels.

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We found an association between elevated Hcy levels and clinical characteristics in first-episode schizophrenic patients, adding further support to the ‘chicken–egg dilemma’ in terms of the heterogeneity of schizophrenia.

Despite the limitations of this study, our results contribute toward the importance of one-carbon metabolism alterations in first-episode schizophrenia. Nevertheless, our results indicate the need for further studies to clarify the role of Hcy in the etiology and prognosis of first-episode schizophrenic patients.

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Future perspective

Future research should attempt to robustly evaluate such a personalized approach as it appears that schizophrenia may be a spectrum of disorders, rather than a discrete disorder. Furthermore, additional research aimed at identifying genetic variants associated with disturbances of biological pathways should be carried out to increase our understanding of this complex disorder and guide individualized treatment programs including nutritional strategies.

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Conflicts of interest

There are no conflicts of interest.

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first-episode schizophrenia; male inpatients; one-carbon metabolism alteration

© 2018 Institute of Psychiatry, Ain Shams University