Does peripheral neuropathy allow for the clinical expression of tardive dyskinesia by unmasking central nervous system changes?

Tardive dyskinesia (TD) is a severe and troubling complication of long-term typical neuroleptic use whose etiology remains obscure. While it is widely believed that central nervous system (CNS) dopamine receptor super-sensitivity is involved in the pathogenesis of the condition, it is unclear why some patients develop TD while others do not. It is proposed that a subclinical peripheral motoneuropathy with consequent enlarging of the motor units may act to unmask neuroleptic-induced CNS changes allowing for the expression of TD. To investigate this hypothesis we examined motor unit size with electrographic examinations in 14 patients (six with mild TD; eight without and all with psychotic illness). There were no differences between the two groups of patients. While the data do not appear to support the hypothesis, a larger study with more severely affected patients is required to more adequately test the hypothesis.

Mood stabilizers and ion regulation.

Understanding the pathogenesis and pathophysiology of bipolar disorder is a prerequisite for accelerating the development of effective therapeutic agents and interventions. One of the best clues to these processes lies in shared mechanisms of action of mood-stabilizing agents. All effective mood stabilizers share the ability to attenuate the influx and intracellular accumulation of sodium in an activity-dependent manner. When coupled with independent observations of aberrant ion regulation in mania and bipolar depression, this shared characteristic is potentially significant. A unified hypothesis is presented in which lithium, valproic acid, and carbamazepine are suggested to produce antimanic effects by modifying ion flux and intracellular ion concentrations.

The ketogenic diet may have mood-stabilizing properties.

The ketogenic diet, originally introduced in the 1920s, has been undergoing a recent resurgence as an adjunctive treatment for refractory epilepsy, particularly in children. In this difficult-to-treat population, the diet exhibits remarkable efficacy with two-thirds showing significant reduction in seizure frequency and one-third becoming nearly seizure-free. There are several reasons to suspect that the ketogenic diet may also have utility as a mood stabilizer in bipolar illness. These include the observation that several anticonvulsant interventions may improve outcome in mood disorders. Furthermore, beneficial changes in brain-energy profile are noted in subjects on the ketogenic diet. This is important since global cerebral hypometabolism is a characteristic of the brains of depressed or manic individuals. Finally, the extracellular changes that occur in ketosis would be expected to decrease intracellular sodium concentrations, a common property of all effective mood stabilizers. Trials of the ketogenic diet in relapse prevention of bipolar mood episodes are warranted.

Trinucleotide repeat expansion in the beta1 subunit of the sodium pump in manic-depression illness: a negative study.

BACKGROUND: Trinucleotide repeats have become a recognized molecular abnormality in a variety of neuropsychiatric conditions. Bipolar illness has been purported to be a possible trinucleotide repeat-associated disease. Since abnormalities in the expression and regulation of the sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) have been documented in bipolar patients and since the beta1 subunit of this pump contains a heterogenous GCC repeat, we decided to investigate the possibility of a repeat expansion in beta1 subunit of Na,K-ATPase in bipolar patients. METHODS: DNA from postmortem temporal cerebral cortex tissue of five bipolar subjects and five matched normal controls and five lyumphoblastoid cells lines from the Old Order Amish bipolar pedigrees and match normal controls were used for this study. The GCC rich region of beta1 DNA was amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: The range of GCC repeat in the beta1 gene is between 7 and 9 in our population. This is not different in bipolar patients from normal controls. LIMITATIONS: This study examined a small number of patients and examined a very limited portion of the locus. CONCLUSION: It appears that there is not an expansion of the GCC repeat in the beta1 gene in bipolar patients.

Open field is more sensitive than automated activity monitor in documenting ouabain-induced hyperlocomotion in the development of an animal model for bipolar illness.

1. Intracerebroventricular (i.c.v.) administration of ouabain to rats induces motor hyper- and hypoactivity that have been hypothesized to model the mania and depression of bipolar illness, respectively. 2. The extent of ouabain-induced change in activity may vary according to the test environment. 3. To determine the degree of differential response to i.c.v. ouabain in the open field and automated activity monitors, the authors examined a large number of animals (n=40) in both environments. 4. I.c.v. ouabain produced a four-fold increase in open field activity versus i.c.v. artificial cerebrospinal fluid (aCSF) (mean +/- SD: 258.7 +/- 316.61 vs. 84.8 +/- 86.16 squares traversed) (t = 2.648, P = 0.011), but did not alter horizontal activity in automated activity monitors (8193.5 +/- 4902.52 vs. 7088.47 +/- 3046.85 beam interruptions) (t = 0.847, P = 0.4). This increase in activity persisted for at least one week (161.0 +/- 186.35 for i.c.v. ouabain vs. 46.1 +/- 47.46 for i.c.v. aCSF, P = 0.065). 5. Open field is superior to automated activity monitors in capturing ouabain-induced hyperlocomotion response.

Completed suicides and emergency psychiatric evaluations: the Louisville experience.

Suicide is one of the most serious outcomes of psychiatric illness, and the most extreme intervention (involuntary hospitalization) can be exercised if this event is likely. Despite this, the rate of suicide has remained fairly consistent at 1.1-1.4%. In an ongoing effort of identifying factors that can predict subsequent suicides, we retrospectively examined the records of individuals who completed suicides in Jefferson County, January 1997 through September 1998, and who were evaluated at the Emergency Psychiatric Service (EPS) at University of Louisville Hospital. Fifteen of the 132 (11.4%) subjects who completed suicide were evaluated at some point in time at EPS. Only 8 (6.1%) were seen within 60 days of the fatal event. This represents less than 0.1% of the total 9,469 patients seen at the EPS during this time period. No specific factors could be identified that predicted imminent suicide. Given the inaccuracy in being able to predict suicide, clinicians need to continue to be vigilant when assessing acutely distressed substance abusing or psychiatric patients.

Ouabain induction of cycling of multiple spike responses in hippocampal slices is delayed by lithium.

Alterations in sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) activity have been associated with changes of mood states and lithium treatment in bipolar illness. We examined the effects of ouabain and lithium on evoked population responses in rat hippocampal slices. In vitro 3.3 microM ouabain induced cycling between epliptiform activity and unresponsiveness in 18.5% of slices. In vitro ouabain, at 1-10 microM, induced epileptiform multiple spike responses. In vivo lithium pretreatment for 10-21 days produced a significant delay in the onset of this ouabain-induced epileptiform activity compared to control animals. These findings are consistent with other work which suggests that Na, K-ATPase inhibition can both activate and suppress excitable tissues and that lithium pretreatment can mitigate these effects. The implications of these results and others regarding the pathophysiology of bipolar illness are discussed.

Antidepressant treatment and neural plasticity.

The use of psychopharmacologic agents in children is complicated by several factors. One important neurobiologic consideration is the relationship of the effect of the medication to ongoing brain development. Although available data are inadequate to address this issue directly, a review of ancillary data suggests that there are theoretical reasons to exercise prudence in prescribing psychopharmacologic agents. For example, the effects of serotonin on neuronal plasticity suggest that agents that can alter serotonergic function may alter neuronal wiring. Although this can occur in any brain, it may be of particular importance in a developing nervous system. The consequences of these induced changes are not clear. Animal studies on the effect of long-term antidepressant administration in immature pups may begin to answer some of the clinical concerns of these observations.

An open study of methylphenidate in bipolar depression.

BACKGROUND: The treatment of bipolar depression is problematic. Mood stabilizing agents are often inadequate, while antidepressants may induce mania or mood destabilization. Methylphenidate has been advocated as an effective antidepressant agent in unipolar depression, and depression secondary to medical illness. Amphetamine administration has been shown to reduce manic behavior. These independent observations suggest that methylphenidate may be a safe and effective agent in bipolar depression. METHODS: Fourteen depressed subjects with DSM-IV bipolar illness and a Hamilton-depression (HAM-D) scale score of at least 15 had methylphenidate added to a stable mood stabilizer regiment. Patients were followed weekly for 4 weeks and then biweekly for an additional 8 weeks. RESULTS: HAM-D scores dropped from 16.9 +/- 1.79 SD at baseline to 9.4 +/- 9.73 on week 12 (p = 0.12, t = 1.84, df= 6) and 9.8 +/- 7.56 on last observation carried forward (LOCF) (p = 0.019, t = 2.8, df = 10). Psychiatric symptom assessment scale (PSAS) scores dropped from 17.9 +/- 5.63 at baseline to 4.8 +/- 7.47 at week 12 (p = 0.016, t = 4.02, df= 4) and 6.3 +/- 6.75 on LOCF (p = 0.007, t = 3.74, df = 7). Three individuals stopped secondary to anxiety, agitation, and hypomania, respectively. CONCLUSION: In this brief, open study, methylphenidate was effective and relatively safe in depressed bipolar subjects.

Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls.

BACKGROUND: A decrease in sodium pump activity in erythrocytes has been associated with manic episodes of bipolar illness relative to euthymic moods. Since red blood cells are long-lived and lack a nucleus, it is likely that a plasma factor is responsible for the observed decrease in sodium pump activity. METHODS: Utilizing a radioimmunoassay, we examined the serum concentrations of the digoxin-like immunoreactive factor (DLIF) in ill and well bipolar patients and compared the values to those of normal controls. RESULTS: DLIF was significantly decreased in manic individuals as compared to normal controls (143.6+/-S.E.M. 20.94 vs. 296.6+/-12.76 pg digoxin equivalents/ml, respectively, F = 4.77, P<0.05), but not compared to euthymic bipolar subjects 213.8+/-86.92, P = 0.77). There were no significant differences in DLIF concentrations between manic and euthymic bipolar individuals (P = 0.8). Since relapse in bipolar patients appears to display a seasonal pattern, we also measured the plasma concentration of this factor over a 12-months period. Normal controls exhibited a seasonal pattern of change in serum DLIF concentrations with a nadir in the winter months. Plasma concentrations of DLIF in bipolar patients did not show a seasonal pattern and maintained low levels throughout the year. LIMITATIONS: Due to the nonspecificity of our antibody, we could measure only total DLIF. Furthermore, it is unclear what the role of circulating DLIF, if any, may be on brain function. CONCLUSION: DLIF may be involved in the pathophysiology of mania.

Alpha 2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals.

BACKGROUND: The pathophysiology of bipolar illness has been associated with changes in transmembrane ion flux and redistribution of biologically active ions. The recent identification of multiple isoforms of Na,K-adenosine triphosphatase (ATPase) alpha and beta subunits raises the possibility of altered pump isoform expression. METHODS: We determined Na,K-ATPase alpha subunit expression in postmortem temporal cortex gray matter from individuals suffering from bipolar disorder, schizoaffective disorder, schizophrenia, and matched normal controls. Quantification of isoform expression was accomplished via densitometric scanning of Western blots utilizing isoform-specific antibodies. RESULTS: Bipolar individuals exhibited a significant reduction in the abundance of the alpha 2 isoform of Na,K-ATPase compared to normal controls. Schizophrenic and schizo-affective brains were not significantly different from normal controls. CONCLUSION: These data suggest that previously observed abnormalities in regulation and distribution of ions in bipolar illness may be related to specific alpha 2 dysregulation.

Clonidine does not potentiate the antipsychotic effects of neuroleptics in chronically ill patients.

Clonidine is a centrally acting antihypertensive and has been prescribed widely for more than 20 years. Because it decreases central norepinephrine activity, clonidine has been investigated as an antipsychotic. In most of the preliminary studies, clonidine was tested as the sole antipsychotic agent. We performed a double-blind, placebo-controlled, crossover study to compare a placebo plus a neuroleptic to clonidine plus a neuroleptic in a group of 16 chronically psychotic patients. Of these 16, 3 dropped out secondary to side effects of the clonidine and 1 withdrew from the study. The clonidine dosage varied from 0.2 to 0.6 mg per day. The concurrent neuroleptic (one of the following: haloperidol, thiothixene, thioridazine, mesoridazine, or fluphenazine) averaged 34 mg per day of haloperidol equivalents. Symptoms were monitored using the Psychiatric Symptoms Assessment Scale. The data provided evidence that a clonidine/neuroleptic combination was not more effective than a neuroleptic alone in this group of patients. These data suggest that the central antinorepinephrine activity of a neuroleptic is not potentiated further by clonidine.