Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies

https://doi.org/10.1016/j.ymgme.2014.10.002Get rights and content

Highlights

  • Folate receptor (FRα) autoantibodies are associated with refractory schizophrenia.

  • These autoantibodies appear to disrupt folate dependent pathways in the brain

  • FRα antibody titers fluctuate in time affecting folate flux to the brain

  • Up- or down-regulation of brain folate influences homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters

  • Daily administration of high-dose folinic acid appears to be beneficial for the control of negative and positive symptoms

Abstract

Background

Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N5-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.

Methods

Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.

Results

Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ2 = 21.6; p < 0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean ± SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p = 0.0002).

A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3–1 mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.

Conclusion

Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

Introduction

Schizophrenia is a severe mental illness affecting 1% of the population. Clinical recognition is characterized by the presence of phases with positive symptoms (delusions, hallucinations, disorganization of thoughts and speech, catatonic behavior), phases with negative symptoms (affective flattening, alogia, avolition) and cognitive impairment [1], [2]. Some neuro-imaging studies documented progressive gray matter loss over 5–10 years [3]. Schizophrenia is a multifactorial disorder carrying a predominant genetic risk as reflected by a positive family history, in addition to environmental risk factors like obstetric complications, social isolation, migrant status and urban life and early exposure to drug abuse like cocaine, amphetamines and cannabis. Schizophrenia fits the model of a complex disorder in which multiple genes interact along with environmental influences, to produce the schizophrenic phenotype. In addition to susceptibility genes involving growth factors participating in nerve growth and development, the encoded proteins by most of the strongest candidate genes are involved in dopamine and glutamate signaling [4], [5], [6]. Beyond the older dopamine hypothesis, the NMDA glutamate receptor hypofunction hypothesis has recently gained more interest [7], [8], [9].

Circumstantial evidence supports the earliest hypothesis that positive symptoms in schizophrenia result from overactive mesolimbic dopamine neurons located in the brainstem (ventral tegmental area) leading to overstimulation of their striatal and limbic projection areas. This was suggested by observations that psychotic episodes can be induced by drugs that increase dopamine, such as amphetamine or cocaine, whereas antipsychotic drugs decrease the effect of dopamine overstimulation by blocking D2 receptors. The negative, cognitive and affective symptoms of schizophrenia result from underactive mesocortical dopamine neurons localized in the brainstem which project to the dorsolateral- and ventromedial prefrontal cortex.

The recent hypothesis of NMDA glutamate receptor hypofunction expanded the earlier dopamine hypothesis by providing an explanation for the differences of overactive mesolimbic neurons versus underactive mesocortical dopamine neurons (Fig. 1). In normal individuals, descending cortical glutamatergic pathways project to and activate NMDA-type glutamate receptors on inhibitory γ-aminobutyric acid interneurons in the brainstem thereby mediating tonic inhibition of mesolimbic dopamine neurons in the ventrotegmental area. In schizophrenic subjects, NMDA receptors on inhibitory interneurons become hypoactive resulting in disinhibition of ventrotegmental dopamine neurons, rendering the mesolimbic dopamine pathways hyperactive which creates the positive symptoms of psychosis. In contrast to mesolimbic dopamine neurons, cortico-brainstem glutamate neurons in normal individuals synapse directly upon the mesocortical dopamine neurons and therefore result in tonic excitation of the mesocortical dopamine neurons and their projection to the prefrontal cortex. In schizophrenic subjects, the cortico-brainstem glutamate projections target hypoactive NMDA receptors upon mesocortical neurons which results in loss of tonic excitation of these mesocortical dopamine neurons and their cortical targets. Underactivity of these mesocortical pathways has been linked to the negative, cognitive and affective symptoms [7], [8], [9], [10], [11]. Evidence in support of the NMDA-receptor hypofunction hypothesis is the fact that several of the known susceptibility genes for schizophrenia reduce NMDA receptor density or decrease glutamate signaling [4]. Moreover, auto-antibodies against NMDA-receptors have been identified in patients presenting with psychotic symptoms as first manifestations [12], [13], [14].

Earlier reports described deranged folate metabolism and disturbed one-carbon transfer associated with schizophrenia [15], [16]. Evidence in support of deranged folate metabolism linked to schizophrenia comes from a study in which one-third of patients with major depression or schizophrenia had unexplained borderline or definite red blood cell folate deficiency that improved after high-dose dl-methyltetrahydrofolate treatment [17].

A report of a girl with mild mental retardation and schizophrenic behavior has identified congenital methylene-tetrahydrofolate reductase (MTHFR) deficiency [18].

Folates represent a family of different interconvertible B-vitamers derived from the oxidized folic acid (Fig. 2). Reduced folates are necessary for neurogenesis and a number of biosynthetic and biochemical processes. Single-carbon groups at different redox states such as N5-formyl-, N10-formyl-, N5,10-methenyl- or N5-methyl-tetrahydrofolate (MTHF) are attached to reduced folates and participate in single-carbon group transfer [19].

N10-formyl-tetrahydrofolate is necessary for de novo synthesis of purines. The synthesized guanosine pool will partly be transformed to GTP, which is the substrate for the enzyme GTP-cyclohydrolase-I, which is the first of 3 enzymatic reactions converting GTP to tetrahydrobiopterin. Thus, N10-formyl-tetrahydrofolate indirectly determines the production rate of tetrahydrobiopterin, which acts as the common co-factor for three rate-limiting enzymes, i.e. tyrosine hydroxylase, tryptophan hydroxylase and NO synthetase, for the production of dopamine, serotonin and NO, respectively.

The vitamin B12 dependent enzyme methionine synthase transfers the one-carbon methyl-group from MTHF to homocysteine to form methionine, which is the substrate for production of the methyl-donor S-adenosyl-methionine (SAM), the activated one-carbon donor participating in over 100 metabolic biochemical reactions [20]. Many receptors participate in folate assimilation. The proton-coupled transporter operates primarily in the gut to absorb folate [21]. The reduced folate carrier and the folate receptor alpha (FRα) are involved in cellular uptake of folate [22]. MTHF, the primary circulating form of folate is transported into the cell by FRα that is also located on the choroid plexus epithelial cells to transport MTHF into the CSF compartment and neural tissues [23].

In this context, a new emerging group of syndromes that are characterized by low CSF MTHF in the presence of normal blood folate levels should be considered. One potential cause is the presence of serum autoantibodies against the FRα protein. These antibodies bind to the FRα on the choroid plexus epithelial cells impairing MTHF transport into the brain [24]. Cerebral folate deficiency (CFD) due to FRα autoimmunity was recently identified in one patient with catatonic schizophrenia whose acoustic hallucinations disappeared after folinic acid treatment [25].

We identified FRα antibodies associated with low CSF MTHF in a 17 year-old girl suffering from severe paranoid schizophrenia who did not respond to neuroleptic and anti-depressive drugs combined with psychotherapy and who attempted suicide several times. This first patient (designated as patient 1 in the present study) recovered remarkably following two months of treatment with high-dose folinic acid. After three months she stopped using neuroleptic and anti-depressive drugs and continued on high dose folinic acid, which resulted in remission and full recovery for more than 8 years now.

This case study and indirect evidence from the literature about the involvement of low folate or deranged one-carbon metabolism in schizophrenia, prompted us to start screening for FRα antibodies among patients with schizophrenia having positive and negative symptoms and responding poorly to neuroleptic drugs and psychotherapy. The reason to screen for FRα antibodies was that metabolic cerebral folate deficiency in most instances remains a hidden disorder, because blood folate status and homocysteine are usually normal. In addition to serum screening, we were able to perform CSF analysis in a number of patients.

Patients with refractory schizophrenia who suffered from FRα autoimmunity were assessed after treatment with high doses of folinic acid.

Section snippets

Methods and patient population

After approval by the hospital's ethics committee, a protocol was adopted to assess all patients with schizophrenia, not responding to conventional drug treatment and psychiatric intervention. The objective of the study protocol was to recruit patients on the basis of clinical features, their impairment to participate in school, education or work and in whom antipsychotic medications were not able to control positive symptoms sufficiently and psychotherapy was not helpful during attempts over

Patient population

At the time of the study the age of the patients varied between 11 and 50 years. All patients suffered from schizophrenia where the initial signs and symptoms dated back from adolescence and since then were characterized by alternating phases of negative or positive symptoms and school reports indicating cognitive impairment. After diagnosis psychotherapeutic intervention and prescription of several antipsychotic drugs for each patient and in some instances anxiolytic and anti-depressive drugs,

Discussion

Exposure to FRα autoantibodies during fetal development and infancy is associated with an increased risk of structural [27], [29], [30] and functional [26], [31] defects. The low CSF MTHF level observed in neurodevelopmental disorders [32] has been attributed to blocking of folate transport by antibodies binding to FRα on the apical side of the choroid plexus [24], [32]. The two different phenotypes, i.e. the previously reported phenotype of infantile autism with or without neurological

Conflict of interest

There is no conflict of interest. Two of the authors (JMS and EVQ) are inventors on a US patent for the detection of FR auto-antibodies issued to the Research Foundation of the State University of New York.

Acknowledgments

This research project has been supported by the Fonds National de la Recherche Scientifique Belgium (FNRS; No. 3.4.540.09.F) to VR and by Autism Speaks (grant No. 8202) to EVQ. The study was approved by the Liege Hospital Ethics Committee. We thank Anahita Rassi and Prof. N Blau of the Division of Metabolism, Zurich University Hospital, for CSF measurements.

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      Apart from those IDFM, CFD has been reported, usually in absence of peripheral deficiency, in children with genetic diseases, particularly mitochondrial disorders, (including Kearns-Sayre Syndrome (KSS) [5,15,16]), Rett syndrome, Aicardi-Goutière's syndrome [5]; but also as an idiopathic syndrome causing psychomotor retardation, hearing loss, cerebellar ataxia, pyramidal syndrome, behavioral abnormalities or epilepsy [2,19]. Some studies suggest autoimmunity might be at cause, based on the detection of serum Frα-antibody, although it remains controversial [2,5,18,20–22]. The exact cause of CFD remains unclear in numerous children with neurologic manifestations.

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