The influence of mania and depression on the pharmacokinetics of lithium: A longitudinal single-case study

doi:10.1016/0165-0327(85)90039-4

Journal of Affective Disorders

Volume 8, Issue 2, March–April 1985, Pages 159-166

https://doi.org/10.1016/0165-0327(85)90039-4 Get rights and content

Abstract

A 28-year-old woman, had, every month, a premenstrual manic-depressive cycle beginning with a hypomanic episode followed by a depression which improved with menstruation. The lithium serum level oscillated in a regular and inverse relationship to the mood changes, although the patient received a constant dosage of lithium: 16.2 mmol/1 per day. The lithium level reached its highest value at the time of the greatest intensity of depression (1.10 mmol/1), and its lowest value during the time of hypomania (0.30 mmol/1), whereas it showed only small oscillations around 0.5 mmol/1 when the patient's mood was normal.

RBC lithium concentration and lithium excretion in the urine followed the same pattern. The daily creatinine excretion was usually within normal limits. It must be hypothesized that there are compartments or stores, to and from which lithium is transported, by mechanisms related to the biological basis of mood changes.

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Microstructural changes of the nucleus accumbens due to increase of estradiol level during menstrual cycle contribute to recurrent manic episodes-A single case study
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Citation Excerpt :
Affective fluctuations during the menstrual cycle have been studied (Akdeniz and Karadağ, 2006). A few previous case presentations of patients, including a report of a woman with bipolar disorder (BPD), showed experienced specific mood episodes in certain periods of the menstrual cycle, such as the premenstrual period (Kukopulos et al., 1985; D’Mello et al., 1993) and luteal phase (Becker et al., 2004). However, the mechanisms underlying the illness phases related to the menstrual cycle have not been investigated.
We examined a rapid-cycling bipolar disorder patient who demonstrated manic episode regularly at around day 7 of the menstrual cycle. We hypothesize that gonadal hormones may induce a state-dependent change in cerebral microstructure and function. Following this hypothesis, the serum levels of estradiol and progesterone were analyzed and diffusion tensor imaging data were examined between the manic and euthymic states of the patient. Estradiol levels increased in the late follicular phase at manic state when compared to the luteal or early follicular phase at euthymic state. DTI results showed that the patient had increased fractional anisotropy values at manic state in the bilateral nucleus accumbens (NAc) and its connected areas, which is a major projection field of the mesolimbic dopamine (DA) system, perhaps reflecting microstructural changes due to neuronal activation related to manic episodes. According to these results, we consider that the mesolimbic DA system of this patient has hypersensitivity to estradiol, and elevation of the estradiol level increases the activity of the dopaminergic system, which in turn may contribute to recurrent manic episodes. Our findings provide a clue for understanding how fluctuations in gonadal hormone may amplify or ameliorate the symptomatology of psychiatric disorders related to the menstrual cycle.
In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005
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The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.
A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.
The LoLi group (< 0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR] = 1.96, p = 0.042), but not depressive (HR = 2.11, p = 0.272) episodes, compared to the combined medium (0.6–0.79 mmol/L) and high lithium level (≥ 0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥ 0.8 mmol/L) for new manic/mixed (HR = 0.96, p = 0.893) or depressive (HR = 0.95, p = 0.922) episodes. The LoOL group (< 10 mg/day) showed a significantly increased risk of depressive (HR = 2.24, p = 0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10–20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR = 0.94, p = 0.895).
Lithium levels ≥ 0.6 mmol/L and olanzapine doses ≥ 10 mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.
Is the polarity of relapse/recurrence in bipolar-I disorder patients related to serum lithium levels? Results from an empirical study
2009, Journal of Affective Disorders
Citation Excerpt :
In addition, while we controlled for the type of the index episode, we did not control for other potentially relevant confounders, such as the number of previous depressive or manic episodes, previous response to lithium or severity of the index episode. We did not examine the possibility that subsyndromal symptoms might have been present at the time of lithium level assessment (Frye et al., 2006) which may either have had an impact on lithium levels by themselves (Kukopoulos et al., 1985) or may have led the treating psychiatrist to increase the lithium dose. Even though our data on the actual doses administered corroborate our main findings, this possibility cannot be ruled out.
Preliminary evidence suggests that the polarity of relapse/recurrence (depressive vs. hypomanic/manic/mixed) in bipolar patients on lithium might be related to serum lithium levels.
Polarity of episodes in 64 bipolar-I patients on lithium monotherapy during a prospective 18-month maintenance trial was predicted from (a) intra-individual oscillations of lithium levels over time and from (b) absolute lithium levels preceding relapse/recurrence.
On an individual basis, depressive (vs. hypomanic/manic/mixed) episodes were mostly preceded by lithium levels above the individual means (p < 0.001). Relapse/recurrence occurring at lithium levels above the overall mean serum level of 0.66 mmol/l was depressive (not hypomanic/manic/mixed) in most cases (odds-ratio = 3.86, p = 0.032). Lithium levels before depressive episodes were numerically higher than before hypomanic/manic/mixed episodes (0.769 ± 0.242 vs. 0.675 ± 0.262 mmol/l, p = 0.13). Cox-regression including current lithium levels as time-dependent predictor essentially confirmed these results.
As patients were not randomized to specific lithium levels, potential confounders could not be completely ruled out. Furthermore, a closer than monthly assessment of both lithium levels and psychopathology would have been desirable to better understand the interplay between lithium levels and new mood episodes.
The results indicate that within the currently accepted therapeutic range (0.4–1.1 mmol/l), the relative risk for depressive vs. hypomanic/manic/mixed relapses/recurrences may be associated with higher lithium levels. Therefore, lithium levels at the lower range of the therapeutic spectrum may be sufficient for the optimal prevention of depressive episodes whereas higher lithium levels within this range may be needed for optimal protection against manic/mixed episodes.
Estradiol and lithium chloride specifically alter NMDA receptor subunit NR1 mRNA and excitotoxicity in primary cultures
2009, Brain Research
Citation Excerpt :
Studies demonstrate that the dominant form of estrogen, estradiol, plays an important role in neuroprotection and enhancement of learning and memory (Henderson et al., 1994). ERT is a subject of debate due to the risk of developing breast cancer. This is marked by an increased incidence of lobular carcinoma in post-menopausal women under ERT (Newcomer et al., 2003) and women suffering from depression during peri-and post-menopause are often prescribed lithium (Burt and Rasgon, 2004; Kukopulos et al., 1985). Estrogen and lithium also affects the dopamine pathway, a pathway implicated in many clinical disorders and neurodegenerative diseases (Morissette et al., 2008; Silverstone, 1985).
Glutamate facilitates calcium influx via NMDAR, and excess calcium influx increases excitotoxicity — a pathological characteristic of neurological diseases. Both 17β-estradiol (E2) and lithium influence NMDAR expression/signaling and excitotoxicity. This led us to hypothesize that combined E2 and lithium will alter NMDAR expression and excitotoxicity. We tested this hypothesis using primary cell cultures from the cortex and hippocampus of C57BL/6J fetal mice pretreated with E2, lithium chloride (LiCl) and combined E2/LiCl for 12, 24 or 48 h. We examined cultures for brain cell type and changes in cell type caused by experimental procedures using glia and neuron gene specific primers. These cultures expressed increased glial fibrillary acidic protein (GFAP) mRNA with low neurofilament-heavy chain (NF-H) mRNA expression. Subsequent analysis of cortical cell cultures indicated that combined E2/LiCl decreased NR1 mRNA expression after a 12 and 48 h treatment period. Combined E2/LiCl also reduced NR1 mRNA expression in hippocampal cultures but only after a 48 h treatment period. LiCl-treated hippocampal cultures also reduced NR1 mRNA expression after a 24 and 48 h treatment. We next examined the response of 48 h pretreated cultures to a toxic level of glutamate. Excitotoxicity was measured using fluorescein diacetate/propidium iodide (FDA/PI) cell viability assay. Results from FDA/PI assay revealed that LiCl pretreatment increased viability for cortical cultures while E2 and combined E2/LiCl reduced viability. All pretreatments for hippocampal cultures failed to increase viability. Our results showed combined E2/LiCl reduced NR1 mRNA and prevented protection against glutamate excitotoxicity in glial primary cultures.
On the physiological function of lithium from a psychiatric viewpoint
2001, Medical Hypotheses
Lithium is a naturally occurring alkali metal, which living organisms ingest from dietary sources and which is also present in trace amounts in the human body. In much higher concentrations, lithium is effective as a medication for mania and mood swings including manic depressive disorders. Many studies have shown that a deficiency in ‘endogenous’ lithium, i.e. lithium in food and drinking water, can lead to defects in growth and development in animals and to grave psychopathological problems in humans. It is therefore conceivable that lithium has an essential function in the physiological regulation of mood and that a subgroup of pathological mood disorders cause a bodily requirement for drastically higher concentrations of lithium in compartments. Taking lithium long-term could have a prophylactic effect on this kind of change in bodily requirements.
Psychiatric Symptoms Across the Menstrual Cycle in Adult Women: A Comprehensive Review
2022, Harvard Review of Psychiatry

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The influence of mania and depression on the pharmacokinetics of lithium: A longitudinal single-case study

Abstract

Zur klinischen Bedeutung der intraerythrozytären Lithiumkonzentration — Ergebnisse einer katamnestischen Studie

Arzneim.-Forsch. (Drug Res.)

Lithium retention in mania

Arch. Gen. Psychiat.

The estimation of lithium in urine

Urinary excretion of lithium in mania

J. Amer. Med. Ass.

The excretion of lithium

Pharmacokinetics of lithium in manic-depressive patients

Acta Psychiat. Scand.

Renal lithium elimination in manic-depressive patients — Initial excretion and clearance

Pharmacopsychiat.