Cecilia A. Peabody

Clinical Relevance of Drug Interactions with Lithium

SummaryAlthough lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions.Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects.Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk.Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all been implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.

CSF amine metabolites and depression

Cerebrospinal fluid (CSF) amine metabolites were measured in 37 male subjects with major depressive disorder. Scores on the Hamilton Rating Scale for Depression (HRSD) correlated significantly with 5-hydroxyindoleacetic acid (5HIAA) and with homovanillic acid (HVA). In addition, the single suicide item of the HRSD correlated significantly with 5HIAA. Further, 5HIAA and HVA correlated significantly with each other. There was a significant positive correlation between HVA and two HRSD items, the depersonalization/derealization item and the paranoid item. Since lumbar CSF metabolite concentrations may reflect central nervous system activity of parent amines, these data suggest a relationship between depression and decreased dopaminergic and serotonergic activity.

Neuroleptics and the elderly.

D r. Cecilia Peabody Neuroleptics are frequently prescribed for nonpsychotic behavior in elderly patients. In one survey, these medications were used primarily for nonspecific aggressive or confusional behavior as well as for sedative-hypnotic purposes. The investigator suggested that such use of neuroleptics may serve institutional rather than individual needs. Elderly patients are at greater risk for developing serious side effects from antipsychotics. Tardive dyskinesia, the incidence of which increases with age, is of greatest concern.* Postural hypotension, anticholinergic effects and oversedation are more dangerous in this age group. The elderly receive 22% of all drug prescriptions, increasing the likelihood of interactions between neuroleptics and other drugs.3 Almost 65% use medications on a regular basis and less than 5% use no drugs at all. The use of multiple drugs taken simultaneously is greater in the elderly and frequently different psychotropics are taken t ~ g e t h e r . ~ These considerations suggest that some present practices in using neuroleptics in elderly patients might be changed.

Desglycinamide-9-arginine-8-vasopressin (DGAVP, Organon 5667) in patients with dementia☆

Vasopressin peptides have been shown to facilitate learning and memory in both animals and humans; however, the effectiveness in humans is controversial. In a double blind parallel group study, 17 demented subjects (either Alzheimers or alcoholic) were given either desglycinamide-9-arginine-8-vasopressin (DGAVP) 92 micrograms intranasally TID or an identical placebo for 1 week after having received 1 week of placebo. To our knowledge, this is the first report of DGAVP being used in subjects with dementia. The DGAVP group had a statistically significant improvement on the Buschke list learning of low imagery words. However, for various reasons discussed in the paper, we feel this finding needs to be replicated before any definite conclusions can be drawn. Since there were no other appreciable behavioral effects of this DGAVP regimen, our results should be considered negative. There was no evidence of any DGAVP-related adverse effects, except for possible weight gain.

Elevated baseline and postdexamethasone cortisol levels: A reflection of severity or endogeneity?

This study investigated whether elevated baseline and postdexamethasone cortisol levels were more strongly related to severity of depression or presence of endogenous symptoms. In 43 inpatients with major depressive disorder, a positive correlation was found between the total score on the Hamilton Rating Scale for Depression and 8.00 a.m. and 4.00 p.m. baseline and 8.00 a.m. and 4.00 p.m. postdexamethasone cortisol levels. Only the 8.00 a.m. postdexamethasone cortisol level was significantly correlated with the number of Research Diagnostic Criteria (RDC) endogenous items present. Despite a statistically significant relationship between severity and endogeneity, our results suggest elevated baseline and postdexamethasone cortisol levels may be more closely related to severity of depression, rather than the presence of a cluster of symptoms referred to as endogenous.

Euthyroid sick syndrome in psychiatric inpatients

Numerous disorders are associated with euthyroid sick syndrome (ESS). This retrospective study examines the incidence and circumstances of ESS among 3188 psychiatric inpatients. There were 324 patients (10.2%) who met strictly defined criteria for ESS. Of these, 95 were hyperthyroxinemic (HT), 6 were hypothyroxinemic, 179 had mildly elevated thyroid-stimulating hormone (HTSH), and 47 had suppressed TSH. All were classified by DSM-III-R discharge diagnoses, encompassing five categories. chi 2 tests of significance of the 95 HT and 179 HTSH subjects revealed the following: 1) no relationship with age or gender; 2) the frequencies of HT and HTSH differed significantly (p < .05 and p < .01, respectively) across the five psychiatric categories; 3) HT frequency was highest in mood disorders (HT in mood versus others p < .02); and 4) HTSH frequency was highest in substance abuse (HTSH in substance abuse versus others p < .02). In conclusion, ESS is common in psychiatric inpatients, especially HT and HTSH; pathophysiologic mechanisms may vary according to psychiatric diagnosis.

Growth hormone response to growth hormone releasing hormone in depression and schizophrenia

Growth hormone releasing hormone, a 44-amino acid peptide (GHRH-44), was administered (1 micrograms/kg i.v.) to 6 normal controls, 10 schizophrenic subjects, and 7 depressed subjects. A significantly lower growth hormone (GH) response was found in the schizophrenic and depressed groups. Two molecular forms of GH, 22K GH and 20K GH, were also measured but did not further differentiate the three groups of subjects.

Antidepressants and the Elderly

The pharmacologic treatment of depression in the elderly is often complicated by cardiovascular disease and other medical illnesses. Both the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors have adverse effects that are potentially dangerous in this age group. Second generation antidepressants may have fewer cardiovascular and anticholinergic side effects, but many do not offer any real advantage over the older drugs. In practical terms, the choice of antidepressants for use in elderly patients will be based largely on their degree of tolerance for unwanted effects.

Blood glucose and insulin response in patients with senile dementia of the Alzheimer's type

We compared community-dwelling SDAT and controls using a standart oral glucose tolerance test(OGTT) under controlled dietary conditions. We measured glucose and insulin levels with fasting and in reponse to a glucose challenge

TRH stimulation test and depression

A thyrotropin-releasing hormone (TRH) stimulation test was performed in 52 male inpatients with major depressive disorder. Twenty-nine percent of the 52 subjects had a delta thyroid-stimulating hormone (delta TSH) less than 5 microU/ml. The cerebrospinal fluid (CSF) amine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA), were measured in 29 subjects, and a dexamethasone suppression test (DST) was performed in 48 subjects. Of the three CSF amine metabolites, only MHPG correlated significantly with baseline TSH and none correlated with delta TSH. The baseline TSH correlated positively with the TSH response at 30 minutes. Neither baseline TSH nor delta TSH correlated with cortisol levels before or after dexamethasone. The correlation between CSF MHPG and serum TSH suggests a relationship between central norepinephrine and baseline TSH.