Brian Toone

Homocysteine, folate, methylation, and monoamine metabolism in depression

OBJECTIVES Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.

Enhancement of recovery from psychiatric illness by methylfolate

Abstract 41 (33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major depression or schizophrenia) had borderline or definite folate deficiency (red-cell folate below 200 μg/l) and took part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic treatment. Among both depressed and schizophrenic patients methylfolate significantly improved clinical and social recovery. The differences in outcome scores between methylfolate and placebo groups became greater with time. These findings add to the evidence implicating disturbances of methylation in the nervous system in the biology of some forms of mental illness.

Cognitive-behavioral therapy for psychogenic nonepileptic seizures A pilot RCT

Objective: To compare cognitive-behavioral therapy (CBT) and standard medical care (SMC) as treatments for psychogenic nonepileptic seizures (PNES). Methods: Our randomized controlled trial (RCT) compared CBT with SMC in an outpatient neuropsychiatric setting. Sixty-six PNES patients were randomized to either CBT (plus SMC) or SMC alone, scheduled to occur over 4 months. PNES diagnosis was established by video-EEG telemetry for most patients. Exclusion criteria included comorbid history of epilepsy, <2 PNES/month, and IQ <70. The primary outcome was seizure frequency at end of treatment and at 6-month follow-up. Secondary outcomes included 3 months of seizure freedom at 6-month follow-up, measures of psychosocial functioning, health service use, and employment. Results: In an intention-to-treat analysis, seizure reduction following CBT was superior at treatment end (group × time interaction p < 0.0001; large to medium effect sizes). At follow-up, the CBT group tended to be more likely to have experienced 3 months of seizure freedom (odds ratio 3.125, p = 0.086). Both groups improved in some health service use measures and on the Work and Social Adjustment Scale. Mood and employment status showed no change. Conclusions: Our findings suggest that cognitive-behavioral therapy is more effective than standard medical care alone in reducing seizure frequency in PNES patients. Classification of evidence: This study provides Class III evidence that CBT in addition to SMC, as compared to SMC alone, significantly reduces seizure frequency in patients with PNES (change in median monthly seizure frequency: baseline to 6 months follow-up, CBT group, 12 to 1.5; SMC alone group, 8 to 5).

Neural correlates of planning ability : frontal lobe activation during the Tower of London test

Single-photon emission computerised tomography (SPECT) was used to investigate whether pre-frontal cerebral blood flow in normal adults is increased during planning activity. A subtraction technique was used in which regional cerebral blood flow (rCBF) was measured in subjects during a computerised version of the Tower of London task. Both rCBF and performance on this task were compared to a motor control condition requiring the same responses and using the same visual display. The level of rCBF was significantly increased in the left pre-frontal cortex during the Tower of London task. In addition, subjects who took more time planning their moves, and less moves to complete a problem had a significantly higher level of rCBF in the left pre-frontal cortex. Subsequent execution latencies for the task were correlated negatively with both left and right rCBF.

Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.

Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimers dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.

Psychopathological syndromes in the functional psychoses : associations with course and outcome

The aim of this study was to identify underlying dimensions of psychopathology in a cohort of patients with functional psychosis of recent onset, and to examine their prognostic value. Factor analysis of the psychopathological features of 166 consecutively admitted patients with functional psychosis of recent onset revealed seven psychopathological dimensions, which explained 63% of the variance. Five of these seven syndromes bore differential associations with subsequent treatment and illness course, independent of: (i) associations with DSM-III-R diagnosis; (ii) associations with other prognostic factors; and (iii) associations with the baseline values of outcome variables. The most striking associations were shown for an early and insidious onset syndrome with affective flattening, which predicted a more disabled course of illness on three of four outcome dimensions, and which was more common in males and unmarried individuals. A second syndrome, characterized by bizarre behaviour, inappropriate affect, catatonia, and poor rapport showed similar, slightly less striking, associations with illness course, as well as with poor pre-morbid social functioning. A third syndrome, characterized by positive psychotic symptoms was to a lesser degree associated with poorer outcome, whereas a fourth syndrome distinguished by manic symptomatology predicted a more benign illness course. A fifth syndrome identified by lack of insight predicted more time in hospital and admission under a section of the Mental Health Act during the follow-up period. A further finding was that dimensional representations of psychopathological features were considerably more useful than categorical representations (DSM-III-R and ICD-10) as predictors of illness course and treatment decisions.

Red cell folate concentrations in psychiatric patients

Red cell folate and vitamin B12 estimations were performed on 243 successively admitted in-patients at a District General Hospital Psychiatric Unit and 42 out-patients (29 attending a lithium clinic). Patients were classified into five diagnostic groups. The mean ages of the manic and schizophrenic patients were lower than of the depressed or euthymic patients but age was not correlated with red cell folate or serum B12 levels in any group. There were 89 (31%) patients with red cell folate below 200 ng/ml and 35 (12%) with concentrations below 150 ng/ml. Significantly more of these low-folate patients were in-patients than out-patients. The mean red cell folate in the depressed patients was significantly lower than in the euthymic, manic and schizophrenic groups. Alcoholics had a similar mean red cell folate to depressed patients which was not quite significantly lower than the other groups. The mean serum B12 level in the alcoholics was, however, significantly raised. There were no significant differences in red cell folate or serum B12 between lithium-treated and untreated euthymic patients. The highest proportions of values below 200 ng/ml and 150 ng/ml were found in depressed and alcoholic patients. Endogenous depressives had the highest percentage of values below 150 ng/ml (folate-deficient) of all psychiatric groups and alcoholic patients. The significance of these findings is discussed.

METHYLATION AND MOOD

S-adenosylmethionine (SAM) has antidepressant properties. The commonest neuropsychiatric complication of severe folate deficiency is depression. These independent observations suggest that methylation in the nervous system may underlie the expression of mood and related processes and may be implicated in some affective disorders; suggest new biological approaches to the understanding and treatment of some affective disorders; and may explain why methionine sometimes aggravates schizophrenia.

Characteristic neurocognitive profile associated with adult attention-deficit/hyperactivity disorder.

BACKGROUND It is now accepted that attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood. However, relative to the considerable literature concerning the profile of neurocognitive deficits associated with this disorder in childhood, equivalent investigations in adult populations have been less common. The current study examined cognitive function in adults diagnosed with ADHD employing well-validated neuropsychological tasks. METHOD Nineteen adult patients who satisfied DSM-IV criteria for ADHD and 19 matched (gender, age and verbal IQ), non-clinical control subjects were recruited. Patients were either unmedicated or had abstained from a psychostimulant medication regime for at least 24 h prior to neurocognitive assessment. A functionally wide-ranging test battery was administered. RESULTS Relative to controls, ADHD adults performed significantly worse on spatial working memory, planning, and attentional-set shifting tests and were significantly slower to respond to target stimuli on the go/no-go task. In contrast, the two subject groups performed equivalently on decision-making and pattern/spatial recognition memory assessments. CONCLUSIONS The demonstration of neuropsychological dysfunction in the adult ADHD cohort provides some support for the validity of this diagnosis in adulthood. In particular, there is broad consistency between the cognitive profile revealed in the current investigation and that previously demonstrated in a study of medication-naïve ADHD children. There is evidence that frontostriatal function is especially disrupted.

Folate deficiency, biopterin and monoamine metabolism in depression

Seven (21%) of 34 patients with a severe DSM-III diagnosis of major depression had red-cell folate levels below 150 ng/ml. This subgroup with folate deficiency had significantly lower CSF 5-hydroxyindoleacetic acid (5HIAA) compared to neurological controls. For all depressed patients red-cell folate was significantly correlated with CSF 5HIAA and homovanillic acid (HVA). CSF tetrahydrobiopterin (BH4) was significantly correlated with CSF 5HIAA and HVA and red-cell folate. Our observations provide further evidence of the links between folate, biopterin and monoamine metabolism in depression.