M.Dhyanne Warner

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.

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.

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.

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.

Prolactin bioassay in schizophrenia before and after neuroleptics

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.

OXYTOCIN AND PROLACTIN RELEASE AFTER ELECTROCONVULSIVE THERAPY: A PILOT STUDY

Abstract This pilot study was conducted to confirm earlier reports of increased prolactin and oxytocin levels after seizures induced by electroconvulsive therapy (ECT). Blood was drawn at 5, 10, 15, 30, and 60 minutes post-seizure from seven psychiatric inpatients with major depressive disorder or mixed bipolar disorder who underwent ECT as part of their clinical treatment. There was a significant increase in prolactin levels at 15 minutes and oxytocin levels at 5 minutes compared with the levels at 60 minutes. These hormone elevations in such a small sample size attest to the robustness of our findings.

Potential abnormalities in molecular forms of growth hormone in schizophrenia: A pilot study

Growth hormone has been investigated in numerous studies involving patients with schizophrenia but has been measured only by radioimmunoassay (RIA). There have been no consistent abnormalities differentiating patients with schizophrenia from normal controls. In the current study, growth hormone (GH) variants were measured by Western blotting techniques, which resulted in the quantitation of 4 GH size variants: 27K (27,000 Daltons), 22K, 20K, and 17K. In the entire sample of 17 schizophrenic subjects, all GH variants were significantly higher than in the 14 normal controls. While there were no significant differences between the 2 groups in RIA GH values, the RIA values were generally higher in the schizophrenic group. In a subset of 12 schizophrenic patients whose RIA values were approximately equal to the controls, both the 27K and 22K GH variants remained significantly higher in the patient group. In the schizophrenic group, none of the GH variants or RIA GH changed significantly after 1 week of treatment with neuroleptic medication. These preliminary results suggest that certain GH forms may be elevated in schizophrenia, but further studies are needed.

Tardive dyskinesia after low-dose haloperidol

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Prolactin bioassay before and after treatment with nortriptyline

Abstract Serum prolactin has been measured in patients with depression before and after treatment with antidepressants. Some, but not all, investigators have reported increased prolactin levels; however, these have been measured by radioimmunoassay (RIA) only. We investigated both serum prolactin RIA and the rat lymphoma Nb2 (Noble strain 2 ) bioassay for prolactin in 13 patients with major depression before and 1 to 2 weeks after treatment with nortriptyline. There were no significant differences with either measure. The relative Nb2 bioactivity of prolactin appears to be unaffected by treatment with nortriptyline.