A Review of the Evidence Base for Nutrition and Nutritional Supplements in Older Adults with Bipolar Disorder: A report from the OABD task force.

OBJECTIVES: To better understand the role of nutrition in older adults (aged 50 years or older) with bipolar disorders (OABD), we conducted a systematic review of the literature and appraise existing evidence. METHODS: Following PRISMA guidelines, we searched databases including Medline/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Register, FDA website, and clinical trial registries through 2019 for eligible reports. The search string combined MeSH terms for bipolar disorder, nutrition and older adults. This was supplemented by snowball searching of references in relevant studies and authors were contacted to request their work where necessary. All included studies were rated with the National Institutes of Health Study Quality Assessment Tools based on study designs. RESULTS: Of 2280 papers screened, ten studies including eight observational and two interventional studies. The topic foci of the papers examined several nutrients, (including vitamin B12, vitamin D, coenzyme Q10, homocysteine, and folate), nutritional deficiencies and biochemical correlates. The prevalence rates of deficiencies varied with specific nutrients (3.7% to 71.6% for Vitamin B12 and 34.6% for Vitamin D), and between inpatient versus outpatient populations. While nutritional interventions appeared to be associated with improvement in both affective and cognitive outcomes, the sample sizes of OABD varied and were generally small. CONCLUSION: While there is evidence for the benefits of nutritional interventions on affective, cognitive and overall outcome in OABD, the quality of the evidence is limited. Our findings underscore the need for high quality studies to inform evidence-based guidelines for nutritional assessment and supplemention in OABD.

Lithium and inositol: effects on brain water homeostasis in the rat.

RATIONALE: Since its earliest use in psychiatry, lithium has been known to alter body water homeostasis. Although lithium is also known to decrease the concentration of inositol, an important brain osmolyte, little is known of the effects of lithium on brain water homeostasis. OBJECTIVE: To determine whether lithium alters brain water homeostasis, and, if so, whether the mechanism involves changes in inositol concentration. MATERIALS AND METHODS: Rats were fed regular food or regular food plus lithium chloride for either 11 days or 5 weeks. Brains were dissected and assayed for tissue water by the wet-dry method and for inositol by gas chromatography-mass spectrometry. RESULTS: We found a statistically significant (p=0.05, corrected) 3.1% mean elevation in frontal cortex tissue water in 5-week lithium-fed rats (86.7+/-3.9%), compared to control rats (83.6+/-2.6%). Inositol concentration correlated inversely with percent tissue water (r=-0.50, p=0.003, corrected) in pooled samples of 5-week lithium-fed rats, and was significantly lower in frontal cortex and hippocampus of 5-week lithium-fed rats, compared to controls. Rats fed lithium for 11 days did not differ significantly from controls on either variable. CONCLUSIONS: This is the first report of a lithium-induced increase in brain tissue water. Although the mechanism is unclear, it does not appear to result from changes in brain inositol concentration or blood sodium concentration. This finding may have implications for the therapeutic or toxic effects of lithium on brain, because increased tissue water can augment cell excitability.

Characterization and quantitative autoradiographic distribution of [3H]acetylcholine muscarinic receptors in mammalian brain. Apparent labelling of an M2-like receptor sub-type.

[3H]Acetylcholine receptor binding characteristics (under muscarinic conditions) have been investigated using membrane binding assays and in vitro receptor autoradiography. In rat, guinea-pig and monkey brain membrane preparations, [3H]acetylcholine binds with high affinity (25-50 nM) to an apparently single class of sites which is differentially distributed across brain regions. The ligand selectivity pattern reveals that the potency of (-)quinuclidinyl benzylate is greater than (greater than) atropine greater than scopolamine greater than oxotremorine greater than carbamylcholine greater than pirenzepine greater than methylcarbamyl-choline = nicotine in competing for [3H]acetylcholine binding sites, indicating that [3H]acetylcholine selectively binds to muscarinic sites under these incubation conditions. Moreover, the low potency of pirenzepine suggests that [3H]acetylcholine does not label a significant proportion of the M1 receptor sub-type but most likely binds to putative M2-like receptor sites. This hypothesis is also supported by the autoradiographic distribution of [3H]acetylcholine binding sites in all species studied here. High densities of [3H]acetylcholine binding sites are seen in various nuclei of the medulla and pons, certain thalamic nuclei, medial septum, laminae III, V and VI of the cortex and just above the pyramidal cell layer of the hippocampus. Such localization is much different from that seen with the non-selective antagonist [3H]quinuclidinyl benzylate and the selective M1 receptor ligand [3H]pirenzepine, although it resembles that of the selective M2 receptor antagonist [3H]AF-DX 116. Thus, [3H]acetylcholine apparently mostly binds with high affinity mainly to non-M1 muscarinic receptor types in mammalian brain tissues. Moreover, the ligand selectivity pattern and in vitro receptor autoradiographic data suggest that at low concentrations (10-20 nM) most of [3H]actylcholine labelled sites are of the M2-like receptor class.

Paralimbic hypoperfusion in unipolar depression.

METHODS: Relative regional cerebral blood flow was measured with SPECT using 99mTc-hexamethylpropyleneamine oxime in 13 patients with severe unipolar depression that was nonresponsive to drug therapy and 11 age-matched nondepressed controls. RESULTS: All patients were clinically depressed and taking antidepressant drugs at the time of the study. The relative blood flow was significantly decreased bilaterally in the frontal cortex, anterior temporal cortex, anterior cingulate gyrus and caudate in the depressed patients compared with the nondepressed healthy controls. The greatest decreases were seen in the paralimbic regions, specifically, the inferior frontal and cingulate cortex. No significant changes were seen in the parietal cortex, occipital cortex or thalami. Psychiatric rating scales correlated poorly with regional blood flow, except for the degree of psychomotor slowing, which was negatively correlated with frontal and cingulate perfusion. CONCLUSION: These findings implicate selective dysfunction of paralimbic brain regions in clinically depressed patients, independent of their medication use, and support the concept of specific neural systems that regulate mood. Recognition of these regional abnormalities may have clinical utility in both the diagnosis and treatment of depression.

Elevated sorbitol concentration in the cerebrospinal fluid of patients with mood disorders.

This study was undertaken to test the hypothesis that a specific pathophysiological mechanism of diabetic neuropathy, namely increased polyol pathway flux, could be operative in patients with bipolar and unipolar mood disorders. Numerous studies have shown abnormalities of carbohydrate metabolism, including high rates of diabetes mellitus, in patients with mood disorders. Several studies have found that peripheral neuropathy is a risk factor for depression in diabetics. Furthermore, increased polyol pathway flux results in elevated sorbitol concentrations in peripheral tissues and cerebrospinal fluid (CSF) of diabetics with neuropathy. The purpose of this study was to determine whether sorbitol concentration is elevated in the CSF of non-medically ill patients with mood disorders. Lumbar punctures were performed on 30 subjects - 10 with bipolar mood disorder, 10 with unipolar mood disorder, and 10 age-matched normal controls, and CSF sorbitol concentrations were measured, using a gas chromatographic-mass spectroscopic technique. The mean+/-standard deviation of CSF sorbitol concentrations differed among the three groups as follows: bipolar (22.9+/-4.6 micromoles/l) > unipolar (19.0+/-2.8 micromoles/l)>normal control (15. 6+/-1.9 micromoles/l). One-way ANOVA showed significant (P=0.0002) differences among the three groups. Post-hoc tests indicated a significant (P<0.05) difference between bipolars and normal controls, bipolars and unipolars, and unipolars and normal controls. Further investigation is needed to determine the pathophysiological significance of this novel finding of elevated sorbitol concentration in the CSF of patients with mood disorders.

Post-training injection of the acetylcholine M2 receptor antagonist AF-DX 116 improves memory.

The present study examined the effect of systemic post-training administration of the acetylcholine muscarinic M2 receptor antagonist AF-DX 116 on the acquisition of two 8-arm radial maze tasks. On a win-stay visual discrimination task, a light cue signalled the location of food in 4 randomly selected maze arms, and rats were required to visit each of the 4 lit arms twice within a trial. Rats were given one trial per day and injected immediately post-training on day 5. AF-DX 116 (0.5 and 1.0 mg/kg) significantly improved win-stay acquisition relative to vehicle-injected controls. On a win-shift task, rats were allowed to visit 4 randomly selected maze arms, followed by a delay period. After the delay, rats were returned to the maze for a retention test in which only those 4 arms not visited prior to the delay contained food. On the test (i.e. drug) trial, rats were removed from the maze after the first 4 choices and injected with AF-DX 116 or vehicle. The retention test was given following an 18 h delay. AF-DX 116 (2.0 mg/kg) significantly improved retention relative to vehicle controls. When the injections were given 2 h post-training, no effect on retention was observed in either task. The results demonstrate that post-training injection of the selective M2 receptor antagonist AF-DX 116 improves memory in a time-dependent manner. The findings may have implications for the cholinergic pharmacotherapy of Alzheimer's disease.

Older adult psychiatric inpatients with non-cognitive disorders should be screened for vitamin B12 deficiency.

OBJECTIVE: Vitamin B12 (B12) deficiency is most prevalent among older adults. Practice guidelines recommend screening older adults with symptoms of cognitive disorder for B12 deficiency. However, guidelines for non-cognitive psychiatric disorders typically do not mention screening older adults for B12 deficiency. The purpose of this study was to determine whether routine screening of older adult psychiatric inpatients for B12 deficiency, regardless of cognitive symptoms, is clinically justified. DESIGN: We conducted a retrospective chart-review study of consecutive inpatient admissions. SETTING: Older Adult Acute Psychiatric Inpatient Unit at the University of Maryland Medical Center from 10/2007-4/2010. PARTICIPANTS: Acute psychiatric inpatients aged ≥50 years who met inclusion criteria (N=374). MEASUREMENTS: Mean (SD) B12 levels and percentages of probable (<180pg/mL) and possible (180-350pg/mL) B12 deficiency as well as characteristics of patients with probable and possible B12 deficiency compared to patients with optimal B12 levels. RESULTS: Mean (SD) B12 levels and percentages of probable and possible B12 deficiency, respectively, for cognitive disorder patients [468 (284) pg/mL, 7.8 % (n=5) and 29.7% (n=19)] and for non-cognitive disorder patients [481(268) pg/mL, 4.8 %(n=15) and 33.2%( n=103)] were not significantly different (t=0.339, df=372, P=0.735; χ2=1.084, df=2, P=0.582, respectively). CONCLUSION: Considering the potential benefits and low costs of screening and treatment, we conclude that it is justified to routinely screen older adult psychiatric inpatients for B12 deficiency whether or not cognitive disorder symptoms are present.

Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: implications for brain energy metabolism and neurotrophic signaling.

The pathophysiology of mood and psychotic disorders, including unipolar depression (UPD), bipolar disorder (BPD) and schizophrenia (SCHZ), is largely unknown. Numerous studies, from molecular to neuroimaging, indicate that some individuals with these disorders have impaired brain energy metabolism evidenced by abnormal glucose metabolism and mitochondrial dysfunction. However, underlying mechanisms are unclear. A critical feature of brain energy metabolism is attachment to the outer mitochondrial membrane (OMM) of hexokinase 1 (HK1), an initial and rate-limiting enzyme of glycolysis. HK1 attachment to the OMM greatly enhances HK1 enzyme activity and couples cytosolic glycolysis to mitochondrial oxidative phosphorylation, through which the cell produces most of its adenosine triphosphate (ATP). HK1 mitochondrial attachment is also important to the survival of neurons and other cells through prevention of apoptosis and oxidative damage. Here we show, for the first time, a decrease in HK1 attachment to the OMM in postmortem parietal cortex brain tissue of individuals with UPD, BPD and SCHZ compared to tissue from controls without psychiatric illness. Furthermore, we show that HK1 mitochondrial detachment is associated with increased activity of the polyol pathway, an alternative, anaerobic pathway of glucose metabolism. These findings were observed in samples from both medicated and medication-free individuals. We propose that HK1 mitochondrial detachment could be linked to these disorders through impaired energy metabolism, increased vulnerability to oxidative stress, and impaired brain growth and development.

Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats.

The prevalence of major depressive disorder (MDD) in adult men is roughly half that of women. Clinical evidence supports a protective effect of androgens against depressive disorders in men. The developing brain is subject to androgen exposure but a potential role for this in depression during adulthood has not been considered. In order to explore this question we treated newborn male rat pups with the androgen receptor antagonist flutamide to block endogenous androgen action and then conducted behavioral tests prior to puberty. Depression-like behaviors were assessed with the Forced Swim Test (FST) and the Sucrose Preference Test (SPT), and anxiety-like behaviors were assessed with the Open Field Test (OFT) and the Novelty-Suppressed Feeding Test (NSFT). Compared to the vehicle-treated controls, neonatal-flutamide treatment caused a significant increase in depression-like behaviors in preadolescent male rats but did not cause any significant difference in anxiety-like behaviors. In separate experiments, male pups with and without flutamide treatment were injected with 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU) from postnatal day (PND) 1 to 4 to label newly produced cells or the hippocampi were Golgi-Cox imbedded and pyramidal neurons visualized. Three lines of evidence indicate neonatal flutamide treatment inhibits hippocampal neurogenesis and neuronal dendritic spine formation in preadolescent male rats. Compared to vehicle controls, flutamide treatment significantly decreased (1) the number of microtubule-associated protein-2+ (MAP-2) neurons in the CA1 region, (2) the number of MAP-2+ neurons in the dentate gyrus (DG) region of the hippocampus, and (3) the density of dendritic spines of pyramidal neurons in the CA1 region. However, there was no effect of flutamide treatment on the number of glial fibrillary acidic protein (GFAP)+ or GFAP+/BrdU+ cells in the hippocampus. This study suggests that the organizational effect of androgen-induced hippocampal neurogenesis is antidepressant.

Uses of intravenous valproate in geriatric psychiatry.

The authors describe the use of intravenous sodium valproate (Depacon) to treat three geriatric inpatients: two acutely manic patients who refused oral medication and one dementia patient with agitation and dysphagia receiving end-of-life care for Alzheimer's disease.

Quantitative autoradiographic distribution of [3H]AF-DX 116 muscarinic-M2 receptor binding sites in rat brain.

The distribution of muscarinic-M2 receptors in rat brain was investigated by in vitro autoradiography using [3H]AF-DX 116, a putative probe for the muscarinic-M2 receptor subtype. Incubation of rat brain coronal sections with 10 nM [3H]AF-DX 116 showed highest binding site densities in discrete areas such as the superior colliculus and certain thalamic and brainstem nuclei, similar to the distribution reported for [2H]acetylcholine/M2 sites. [3H]AF-DX 116 site densities were markedly lower in forebrain areas such as cortex, striatum, and hippocampus, in contrast to the distribution seen for [3H]pirenzepine-M1 binding sites, which were concentrated in these forebrain areas; however, differential patterns of labeling were observed for the two muscarinic-M2 probes, [3H]AF-DX 116 and [3H]acetylcholine, in the hippocampal formation. Although [3H]AF-DX 116 binding was broadly distributed in multiple subfields of the hippocampus, [3H]acetylcholine binding was discretely distributed in a manner resembling that of acetylcholinesterase staining. This suggests the existence of muscarinic-M2 subtypes in the CNS, especially in the hippocampal formation.

Electroconvulsive therapy for epilepsy and major depression.

In this first report of electroconvulsive therapy (ECT) for the simultaneous treatment of seizures and depressive episodes, the authors discuss the use of ECT in the treatment of complex-partial seizures and major depression in a geriatric patients who refused antidepressant and antiepileptic medication. ECT has numerous anticonvulsant effects, including elevated seizure threshold and decreased seizure duration, which make it a useful adjunctive therapy in epilepsy that is refractory or not amenable to treatment with medication.

Characterization of [3H]AF-DX 116 binding sites in the rat brain: evidence for heterogeneity of muscarinic-M2 receptor sites.

This study shows that [3H]AF-DX 116 binds specifically, saturably, and with high affinity to putative muscarinic-M2 receptor sites in the rat brain. In homogenates of the hippocampus, cerebral cortex, striatum, thalamus, and cerebellum, [3H]AF-DX 116 appears to bind two subpopulations of muscarinic sites: one class of higher affinity sites (Kd less than 4.0 nM) and one class of lower affinity sites (Kd greater than 50 nM, except in the cerebellum). The apparent maximal capacities (Bmax) of [3H]AF-DX 116 sites in forebrain tissues ranged between 34 and 69 fmol/mg protein for the higher affinity site, and between 197 and 451 fmol/mg protein for the lower affinity site. In cerebellar homogenates, the maximal capacity of [3H]AF-DX 116 binding sites was 10.4 +/- 0.4 (Kd = 1.9 +/- 0.2 nM) and 39.1 +/- 2.6 (Kd = 26 +/- 7 nM) fmol/mg protein for the higher and the lower affinity site, respectively. Determination of the Kd for the higher and lower affinity [3H]AF-DX 116 sites from association and dissociation constants yielded similar values to those obtained from the saturation data. The ligand selectivity pattern reveals that AF-DX 116 is more potent than (-)QNB greater than atropine greater than methoctramine greater than 4-DAMP greater than gallamine greater than NMS greater than carbamylcholine greater than oxotremorine greater than pirenzepine much greater than nicotine in competing for the higher affinity [3H]AF-DX 116 sites. With few exceptions, the pattern was similar for the lower affinity sites.(ABSTRACT TRUNCATED AT 250 WORDS)

GSK-3beta in cerebrospinal fluid of schizophrenia patients.

Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970's with few definitive results. We have recently found 40% reduced protein levels of GSK-3beta in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3beta was not successful. In this study we aimed to find whether the reduction in brain GSK-3beta is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3beta protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients' postmortem brain.