Nonalcoholic Wernicke-Korsakoff Syndrome Resulting From Psychosis.

ABSTRACT: Wernicke encephalopathy (WE) results from thiamine deficiency. If undiagnosed or inadequately treated, WE evolves into Korsakoff syndrome (KS). We herein report a case of nonalcoholic Wernicke-Korsakoff syndrome (WKS) that resulted from malnutrition due to psychosis in a 42-years-old male patient. Thiamine deficiency was secondary to severe malnourishment due to poisoning delusions and daily life disorganization in a patient with previously unrecognized schizophrenia. Besides the presence of WE's classic triad of signs, brain magnetic resonance imaging showed also typical thalamic lesions. Furthermore, the patient also presented anterograde and retrograde amnesia, executive dysfunction, and confabulations, compatible with KS being already present. Intravenous treatment with thiamine was given for 37 days. Improvement in cognitive functions and brain imaging alterations was evident. Nevertheless, persistent WKS deficits were present. This case highlights the multiplicity of etiologies of WKS, namely, psychiatric, and its debilitating consequences if not promptly recognized and treated.

Thiamine deficiency in the outpatient psychiatric oncology setting: A case series.

OBJECTIVE: B vitamins are essential for the functioning of the nervous system. Vitamin B1 (thiamine) deficiency is associated with neuropsychiatric syndromes such as Wernicke's encephalopathy (WE), which, if untreated, has an estimated mortality of 17-20%. Although the prevalence of thiamine deficiency in the general population is difficult to estimate, it is being increasingly recognized in oncology, especially in the inpatient setting. We describe three cases of thiamine deficiency (TD) in the outpatient psychiatric oncology setting. METHOD: Retrospective chart review of three adult patients, who were seen in the psychiatric oncology clinic and found to have TD on laboratory testing, was done. Patient, disease, and thiamine treatment-related information were obtained, and descriptive statistics were used to analyze the data. RESULTS: The average age was 59 years, mean body mass index (BMI) was 22.00 ± 4.58 (mean ± SD), and mean thiamine level was 59.10 ± 7.69 that ranged from 45 to 68 nmol/L (normal thiamine level reference: 70-180 nmol/L). None of the patients had brain imaging nor cerebrospinal fluid analysis. Risk factors such as unbalanced nutrition, prior GI surgery, renal disease, and chemotherapy were noted. SIGNIFICANCE OF RESULTS: TD can have a multifactorial etiology in oncology. Identification of TD in both inpatient and outpatient setting is important. Our report highlights how early identification of TD in the outpatient setting can help prevent further clinical progression.

Social vulnerability: The connection between psychiatric disorders and thiamine deficiency in pregnant women.

The evaluation of thiamine and its derivative phosphate esters levels in pregnant women in rural communities can contribute not only for understanding the specific characteristics of this population regarding nutritional aspects, but also for clarifying the relations of psychiatric manifestations and a vitamin deficit. In the present work we assessed sociodemographic variables, psychiatric parameters and thiamine and its derivative in the whole blood of women in a rural, low-income community in Brazil. A case-control study was done. 94 women were divided in groups using the trimesters of pregnancy as a criterion: each trimester, 1st, 2nd and 3rd had 17, 37 and 38 women, respectively. A control group of non-pregnant women (n-39) was also included. Symptoms of anxiety and depression were assessed using the HAMA Scale and Beck Inventory, respectively. The thiamine and its phosphorylated derivatives concentrations were determined in whole blood samples using the HPLC method. The results suggest that physiological mechanisms linked to the metabolic pathways of thiamine may play a role in some neurobiological substrate involved in the regulation of emotional state. Thus, social vulnerability is identified as an important factor to be considered in the evaluation of the mental health of pregnant women living in rural communities.

Thiamine deficiency in a patient with recurrent renal cell carcinoma who developed weight loss with normal appetite and loss of energy soon after nivolumab treatment.

BACKGROUND: Nivolumab has become an effective treatment option for cancer in various sites; however, this drug may cause immune-related adverse effects due to its mechanism of action. Furthermore, little has been reported on thiamine deficiency (TD) in patients receiving nivolumab treatment. METHOD: From a series of cancer patients, we reported a patient with recurrent renal cell carcinoma who developed TD after the start of nivolumab treatment. RESULTS: A 74-year-old man with recurrent renal cell carcinoma was referred to the psycho-oncology department as he had lost about 4 kg and displayed a loss of energy after four cycles of nivolumab treatment. Psychiatric interviews revealed a decrease in energy. Neurological examination did not reveal any impairment in consciousness, ataxia, or ocular symptoms. He did not develop appetite loss. The malabsorption or overconsumption of some nutrients is thought to occur due to the rapid loss of weight; thus, a reduction in vitamin B1, which has a short storage period in the body and is often deficient in cancer patients, was suspected. The diagnosis of TD was supported by the patient's abnormally low serum thiamine level. SIGNIFICANCE OF RESULTS: In patients treated with nivolumab, it is necessary to pay careful attention to TD when proceeding with the treatment. It is hoped that future research may reveal the link between nivolumab administration and TD.

Memantine ameliorates learning and memory disturbance and the behavioral and psychological symptoms of dementia in thiamine-deficient mice.

Several studies have reported on the beneficial effects of memantine on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease. However, the effects of memantine on BPSD-like behaviors in animals have not been well addressed. Here, the effects of memantine on memory disturbance and BPSD-like behaviors were evaluated in thiamine-deficient (TD) mice. Memantine (3 and 10 mg/kg, b.i.d.) was orally administered to ddY mice fed a TD diet for 22 days. During the treatment period, the forced swimming test, elevated plus-maze test, passive avoidance test, and locomotor activity test were performed. Neurotransmitter levels in the brain were analyzed after the treatment period. Daily oral administration of memantine ameliorated the memory disturbances, anxiety-like behavior, and depression-like behavior observed in TD mice. Memantine did not have a significant effect on monoamine levels, but increased glutamate levels in the hippocampus in TD mice. These results suggest that memantine prevents or suppresses the progression of BPSD-like behaviors that develop due to TD. This effect may be mediated in part by the enhancement of glutamatergic neuron activity in the hippocampus.

Thiamine deficiency in the bereaved after cancer-related spousal loss.

OBJECTIVE: Thiamine deficiency (TD) is recognized in various kinds of disease with associated loss of appetite including cancer. However, it has not been recognized to date in bereaved partners after spousal loss from cancer. METHOD: From a series of bereaved partners who lost a spouse to cancer, we report on those who developed TD after bereavement. RESULT: Case 1 was a 57-year-old woman who sought consultation at our "bereavement clinic." Her husband had been diagnosed with pancreatic cancer one year earlier and had died one month previously. At the first visit, she was observed to suffer depression, anxiety, and decreased appetite. Neurological, blood, and biochemical examinations did not reveal any noteworthy findings. She was diagnosed with uncomplicated bereavement. Detailed examination revealed that her appetite had been markedly decreased for approximately five weeks. The diagnosis of TD was supported by her abnormally low serum thiamine level. Case 2 was a bereaved 73-year-old male who had lost his wife to hypopharyngeal cancer one month previously after a five-year illness. He had shown a lack of energy for the month preceding his wife's death, but because there was no improvement after her death, his family recommended he seek consultation at our "bereavement clinic." He was suffering from major depressive disorder. Detailed examination revealed that his appetite had been decreased for more than two weeks. Again, the diagnosis of TD was supported by his abnormally low serum thiamine level. SIGNIFICANCE OF RESULTS: These reports demonstrate that there is a possibility that bereaved could develop TD after the loss of a loved one. TD should be considered whenever there is a loss of appetite lasting for more than 2 weeks, and medical staff should pay careful attention to the physical condition of the bereaved to prevent complications because of TD.

Wet Beriberi Associated with Hikikomori Syndrome.

Wet beriberi, characterized by high cardiac output with predominantly right-sided heart failure and lactic acidosis, is a disease caused by thiamine deficiency, and is rarely seen in modern society. However, patients with social withdrawal syndrome, also known as hikikomori syndrome, may be a new population at risk of thiamine deficiency. Hikikomori syndrome, first recognized in Japan, is becoming a worldwide issue. A 39-year-old Japanese patient was brought to our hospital, with a 3-week history of progressive shortness of breath and generalized edema. The patient had right-sided high-output heart failure, lactic acidosis, and Wernicke-Korsakoff syndrome. Because of his history of social isolation, we diagnosed hikikomori syndrome according to the Japanese government's definition, which is as follows: lifestyle centered at home; no interest or willingness to attend school or work; persistence of symptoms beyond 6 months; and exclusion of other psychiatric and developmental disorders. Considering his diagnosis of hikikomori syndrome and social isolation, we suspected malnutrition, particularly thiamine deficiency, and successfully treated him. Clinicians should be aware of the potential risk of thiamine deficiency associated with hikikomori syndrome and initiate thiamine replacement in cases of high-output heart failure associated with lactic acidosis.

Comparative effects of EtOH consumption and thiamine deficiency on cognitive impairment, oxidative damage, and ß-amyloid peptide overproduction in the brain.

The effects of chronic EtOH consumption, associated or not with thiamine deficiency (TD), on cognitive impairment, oxidative damage, and ß-amyloid (Aß) peptide accumulation in the brain were investigated in male C57BL/6 mice. We established an alcoholic mouse model by feeding an EtOH liquid diet, a TD mouse model by feeding a thiamine-depleted liquid diet, and an EtOH treatment associated with TD mouse model by feeding a thiamine-depleted EtOH liquid diet for 7 weeks. The learning and memory functions of the mice were detected through the Y-maze test. Biochemical parameters were measured using corresponding commercial kits. The Aß expression in the hippocampus was observed by immunohistochemical staining. Several results were obtained. First, EtOH significantly reduced cognitive function by significantly decreasing the Glu content in the hippocampus; increasing the AChE activity in the cortex; and reducing the thiamine level, and superoxide dismutase (SOD), glutathione peroxidase (GPx), and choline acetyltransferase (ChAT) activities in both the hippocampus and cortex. The treatment also increased the levels of malondialdehyde (MDA), protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), and nitric oxide (NO) and the activities of total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS), and monoamine oxidase B (MAO-B). Furthermore, EtOH enhanced the expression levels of Aß1-42 and Aß1-40 in the hippocampus. Second, TD induced the same dysfunctions caused by EtOH in the biochemical parameters, except for learning ability, 8-OHdG content, and GPx, tNOS, and AChE activities in the cortex. Third, the modification of MDA, protein carbonyl and NO levels, and GPx, iNOS, ChAT, and MAO-B activities in the brain induced by chronic EtOH treatment associated with TD was greater than that induced by EtOH or TD alone. The synergistic effects of EtOH and TD on Aß1-40 and Glu release, as well as on SOD activity, depended on their actions on the hippocampus or cortex. These findings suggest that chronic EtOH consumption can induce TD, cognitive impairment, Aß accumulation, oxidative stress injury, and neurotransmitter metabolic abnormalities. Furthermore, the association of chronic EtOH consumption with TD causes dramatic brain dysfunctions with a severe effect on the brain.

Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility.

BACKGROUND: Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol-related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. METHODS: Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD (PTD-moderate acute stage); moderate PTD (PTD-early acute stage); moderate PTD followed by CET (PTD-CET); moderate PTD during CET (CET-PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor (BDNF) and thalamic pathology. RESULTS: Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. CONCLUSIONS: These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD.

Hypomagnesaemia and its potential impact on thiamine utilisation in patients with alcohol misuse at the Alice Springs Hospital.

INTRODUCTION AND AIMS: Alcohol rapidly reduces thiamine among alcohol-dependent individuals. Poor diet and alcohol's impact on absorption, storage, activation and excretion of thiamine are thought to be the mechanisms. Previous literature identifies magnesium as an important cofactor in thiamine utilisation, which might also be compromised in alcohol dependent patients. The aim was to describe the thiamine status and clinical profile for a sample of heavy alcohol users entering the Alice Springs Hospital in the Northern Territory of Australia and to examine the relationship between thiamine deficiency, magnesium deficiency and cognitive functioning. DESIGN AND METHODS: Cross-sectional study examining thiamine pyrophosphate (TPP) and magnesium concentrations for a sample of 62 males and 43 females (N = 105; n = 88 Aboriginal, n = 13 non-Indigenous). Cognition was assessed using the Rowland Universal Dementia Assessment Scale. RESULTS: TPP concentrations were within or above the reference range. Aboriginal patients had significantly lower TPP than non-Indigenous patients. A marginally significant difference was found between individuals with thiamine supplementation recorded within the previous 20 days compared with those without. Mean serum magnesium was in the low normal range with magnesium deficiency (i.e. <0.80 mmol L(-1)) present in 48% of those tested. Serum magnesium (but not TPP) concentrations correlated positively with cognitive test scores. DISCUSSION AND CONCLUSIONS: Despite increased exposure to risk factors for Wernicke Korsakoff Syndrome, no patient had TPP concentrations below the reference range. High patient readmission and aggressive thiamine treatment policies may explain this finding. However, low magnesium may be prevalent and could contribute to impaired thiamine utilisation.

Beyond alcoholism: Wernicke-Korsakoff syndrome in patients with psychiatric disorders.

OBJECTIVE: Wernicke encephalopathy and Korsakoff syndrome (the combined disorder is named Wernicke-Korsakoff syndrome [WKS]) are preventable, life-threatening neuropsychiatric syndromes resulting from thiamine deficiency. WKS has historically been associated with alcoholism; more recently, it has been recognized in patients who have anorexia nervosa or have undergone bariatric surgery for obesity. However, patients with nutritional deficiencies of any origin are at risk for WKS. We present clinical histories and neuroimaging data on 2 young adults with underlying psychiatric disorders who became malnourished and developed WKS. METHODS: A young woman with bipolar disorder and somatization disorder was hospitalized for intractable vomiting. A young man with chronic paranoid schizophrenia developed delusions that food and water were harmful, and was hospitalized after subsisting for 4 months on soda pop. RESULTS: Acute, life-threatening Wernicke encephalopathy was confirmed in both patients by brain magnetic resonance imaging showing classic thalamic injury. The patients were left with persistent cognitive and physical disabilities that were consistent with Korsakoff syndrome. CONCLUSIONS: Failure to suspect a vitamin deficiency led to permanent cognitive and physical disabilities that may necessitate lifelong care for these patients. The neuropsychiatric consequences could have been prevented by prompt recognition of their thiamine deficiency.

[A case of thiamine deficiency with psychotic symptoms--blood concentration of thiamine and response to therapy].

We report the case of a 63-year-old woman with thiamine deficiency who showed auditory hallucinations, a delusion of persecution, catatonic stupor, and catalepsy but no neurological symptoms including oculomotor or gait disturbance. Brain MRI did not show high-intensity T2 signals in regions including the thalami, mamillary bodies, or periaqueductal area. Her thiamine concentration was 19 ng/mL, only slightly less than the reference range of 20-50 ng/mL. Her psychosis was unresponsive to antipsychotics or electroconvulsive therapy, but was ameliorated by repetitive intravenous thiamine administrations at 100-200 mg per day. However, one month after completing intravenous treatment, her psychosis recurred, even though she was given 150 mg of thiamine per day orally and her blood concentration of thiamine was maintained at far higher than the reference range. Again, intravenous thiamine administration was necessary to ameliorate her symptoms. The present patient indicates that the possibility of thiamine deficiency should be considered in cases of psychosis without neurological disturbance and high-intensity T2 MRI lesions. Also, this case suggests that a high blood thiamine concentration does not necessarily correspond to sufficient thiamine levels in the brain. Based on this, we must reconsider the importance of a high dose of thiamine administration as a therapy for thiamine deficiency. The validity of the reference range of the thiamine concentration, 20-50 ng/mL, is critically reviewed.

Delayed language development due to infantile thiamine deficiency.

The aim of this study was to investigate the language development of 20 children who had been exposed to thiamine (vitamin B(1)) deficiency in infancy due to feeding with soy-based formula that was accidentally deficient of thiamine. In this case-control study, 20 children (12 males, eight females; mean age 31.8mo [SD 4.1], range 24-39mo) who were fed thiamine-deficient formula in infancy were compared with 20 children (12 males, eight females; mean age 32.2mo [SD 3.9], range 25-39mo) fed with other milk sources and matched for age, sex, and maternal education. Receptive and expressive language development was assessed with the Preschool Language Scale, 3rd edition. Other assessments included mental development (Bayley Scales of Infant Development, 2nd edition), evaluation for autistic spectrum disorders, and neurological examination. Motor development was compared by age at independent walking. The study and control groups differed significantly in the expressive communication (p<0.001) and auditory comprehension language subscales (p<0.001), the Mental Developmental Index score (p<0.001), and age at independent walking (p=0.001). A significant correlation was found between the receptive language score and age at independent walking, i.e. poorer language associated with later walking (r=-0.601, p=0.005). The conclusion was that thiamine deficiency in infancy could affect language development in childhood.

Molecular genetics of alcohol-related brain damage.

AIMS: In the scientific literature it has been repeatedly hypothesized that there is a heritable susceptibility to thiamine deficiency comparable to other hereditary metabolic disorders. The aim of this paper is to review the most recent knowledge on the genetic susceptibility to the development of alcohol-related Wernicke-Korsakoff syndrome (WKS). METHODS: A literature review was carried out looking at the molecular genetics studies performed in alcohol-dependent patients affected by WKS. RESULTS: A genetic component in the pathogenesis of WKS has been postulated since the late seventies. Since then, very few genetic studies have been carried out on candidate genes such as thiamine-dependent enzymes, alcohol-metabolizing enzymes and GABA receptors. The findings are controversial and not conclusive. Several authors reported the important role of the thiamine transporters in the pathogenesis of the thiamine deficiency disorders. Our findings on SLC19A2 and SLC19A3 suggest a potential role of these two genes in the pathophysiology of alcohol-related thiamine deficiency but further studies need to be carried out. CONCLUSIONS: The WKS may be a very complex, multifactorial disorder where the interaction of multiple genes and environment plays an important role in the pathogenesis. However, it is still plausible that megaphenic gene effects are responsible for WKS susceptibility and the thiamine transport genes are good candidates for having such a role. Further genetic studies are definitely needed to investigate the association with candidate genes or linkage with hot spot areas.

[Thiamine deficiency caused by malnutrition: a rare cause?]. / Thiaminedeficiëntie veroorzaakt door malnutritie; een zeldzame oorzaak?

A 50-year-old man was admitted to our psychiatric clinic with symptoms of depression, comorbid neurological disturbances and cardiomyopathy. The condition was diagnosed as beriberi and Korsakov's syndrome, on the basis of thiamine deficiency. The patient's diet was unbalanced and restricted, but he was not an alcohol abuser. Thiamine suppletion led to a partial remission of symptoms. If a patient presents with depressive symptoms combined with neurological disturbances or heart irregularities, the Wernicke-Korsakov syndrome should be ruled out, even if the patient does not abuse alcohol. If in doubt, always opt for thiamine suppletion.

Increasing hippocampal acetylcholine levels enhance behavioral performance in an animal model of diencephalic amnesia.

Pyrithiamine-induced thiamine deficiency (PTD) was used to produce a rodent model of Wernicke-Korsakoff syndrome that results in acute neurological disturbances, thalamic lesions, and learning and memory impairments. There is also cholinergic septohippocampal dysfunction in the PTD model. Systemic (Experiment 1) and intrahippocampal (Experiment 2) injections of the acetylcholinesterase inhibitor physostigmine were administered to determine if increasing acetylcholine levels would eliminate the behavioral impairment produced by PTD. Prior to spontaneous alternation testing, rats received injections of either physostigmine (systemic=0.075 mg/kg; intrahippocampal=20, 40 ng/muL) or saline. In Experiment 2, intrahippocampal injections of physostigmine significantly enhanced alternation rates in the PTD-treated rats. In addition, although intrahippocampal infusions of 40 ng of physostigmine increased the available amount of ACh in both pair-fed (PF) and PTD rats, it did so to a greater extent in PF rats. The increase in ACh levels induced by the direct hippocampal application of physostigmine in the PTD model likely increased activation of the extended limbic system, which was dysfunctional, and therefore led to recovery of function on the spontaneous alternation task. In contrast, the lack of behavioral improvement by intrahippocampal physostigmine infusion in the PF rats, despite a greater rise in hippocampal ACh levels, supports the theory that there is an optimal range of cholinergic tone for optimal behavioral and hippocampal function.

Functional vulnerability of developing central nervous system to maternal thiamine deficiencies in the rat.

Thiamine deficiency (B1 vitamin) was induced during three periods of rat central nervous system (CNS) ontogenesis. Females were fed a thiamine deficient diet such that developing offspring were exposed either to pre-, peri-, or postnatal thiamine deficiency. To control the effects of undernourishment generated by different thiamine deficiencies, every treatment group had its own pair-fed control pup from a non drug-treated but undernourished dam. Seven different developmental abilities (exploratory activity, emotional reaction, hind paws lifting reflex, wire grasping times, crawling and leap execution latencies, and nociception) were recorded in the offspring from the 10th to the 45th postnatal day. The vulnerability of developing brain to the specific lack of B1 vitamin increases from prenatal (28%) to perinatal (43%) and postnatal periods (57%).

Behavioral and neurochemical alterations following thiamine deficiency in rodents: relationship to functions of cholinergic neurons.

Memory deficits are induced during the late stage (20-25 days) of thiamine-deficient (TD) feeding. In this review, the role of cholinergic neurons on the memory deficit induced by TD feeding are summarized. Although memory deficit cannot be suppressed by an injection of thiamine once it appears, such impairment was found to be protected by early treatment with thiamine during TD feeding. Administration of muscarinic M(1) agonist McN-A-343 reversed the memory deficit observed in TD mice, although the muscarinic M(2) antagonist methoctramine did not. The "kampo" (traditional herbal) medicine, "kami-untan-to" (KUT), protected against the memory deficit observed in TD mice. Choline acetyltransferase (ChAT) fluorescence intensity, a marker of presynapse of cholinergic neurons, was decreased in the cortex and hippocampus at an early stage (14th day) of TD, and it was decreased in a wide range of brain areas at a late stage (25th day) of TD. Early KUT treatment inhibited the reduction of ChAT in the hippocampus of TD mice. These findings suggested that the memory deficit may be caused by a reduction in the cholinergic function at an early stage of TD, and that the activation of cholinergic neurons may play an important role in the improvement of TD-induced memory deficit.

Characteristics of depressive behavior induced by feeding thiamine-deficient diet in mice.

We produced thiamine-deficient (TD) mice by TD diet treatment. The growth curve of mice on TD feeding was sharply increased until on the 10th day and subsequently the body weight gradually decreased. The mortality rate in mice was about 67% on the 30th day after the start of TD feeding. We performed the forced swimming test on the 10th and 20th day after the start of TD feeding. The duration of immobility in the forced swimming test was increased on the 20th day of TD feeding. Locomotor activity and motor co-ordination between the pair-fed control group and TD group on the 20th day of TD feeding were not significantly changed. Only a single injection of thiamine HCI (50 mg/kg, s.c.) on the 10th day after the start of a TD diet shortened the increased duration of immobility in the forced swimming test on the 20th day after the start of TD feeding. Whereas these reversal effects of thiamine treatment on the 20th day were not found when the treatment was given on the 19th day after the start of a TD diet. On the 20th day after the start of TD feeding, the increased duration of immobility time induced by TD was shortened by chronic administration of the tricyclic antidepressant imipramine (10 mg/kg, i.p.). These results suggested that behavioral changes in the forced swimming test might be involved in the degeneration of serotonergic and noradrenergic neurons.