Lithium

Nervous system

There has been a spate of publications describing the neuroprotective effects of lithium. By inhibiting glycogen synthase kinase-3, lithium inhibits tau hyperphosphorylation and protects against β-amyloid-induced cell death, suggesting a possible role in the treatment of Alzheimer’s disease [ , ]. Studies in mice and cell lines show that lithium reduces gp120-associated neurotoxicity, suggesting that it may be useful in preventing progression of HIV-associated cognitive deterioration [ ]. Low-dose lithium reduced infarct volume and neurological deficits in a rat model of transient focal cerebral ischemia [ ].

Several animal and in vitro studies have demonstrated a neuroprotective effect of lithium against a wide array of toxic insults [ ]. In humans, grey matter density was greater in 20 lithium-treated patients compared with eight patients not taking lithium and 29 matched healthy controls, particularly in the right anterior cingulate [ ]. Furthermore, there was a bilateral increase in the volume of the hippocampus and hippocampal head in patients with bipolar disorder who took lithium for 1–8 weeks compared with unmedicated patients and healthy controls [ ]. While these studies suggest a neurorestorative effect of lithium, it has not been clearly demonstrated that the observed increases in the sizes of brain structures are not merely related to increases in water content secondary to lithium accumulation.

Overall, the evidence that lithium has neuroprotective and neurotropic effects through a variety of mechanisms is striking [ ], although whether those findings will evolve into therapies of practical clinical value remains to be seen.

Chronic cluster headache has responded to lithium [ ].

Sensory systems

In cultured mouse retinal ganglion cells, lithium supported the survival and regeneration of axons [ ]. This led the authors to the very speculative suggestion that lithium might be useful in treating conditions such as glaucoma, optic neuritis, and other neuron loss disorders.

Endocrine

Lithium blocks the release of iodine and thyroid hormones from the thyroid and has been used to treat hyperthyroidism, as an adjunct to radioiodine therapy [ ] and in metastatic thyroid carcinoma [ ]. However, it can also cause hyperthyroidism. Lithium enhanced the efficacy of radioiodine in 23 patients [ ], but was ineffective in a larger comparison of lithium (n = 175) or radioiodine alone (n = 175) [ ]. In 24 patients with Graves’ disease, lithium attenuated or prevented increases in thyroid hormone concentration after methimazole withdrawal and radioiodine treatment [ , ].

In a case of amiodarone-induced thyrotoxicosis that did not respond to antithyroid drugs and glucocorticoids, low-dose lithium normalized thyroid function [ ].

Lithium has been used, with several other drugs, to treat four patients with amiodarone-associated thyrotoxicosis, but the drugs were ineffective in two patients, who required thyroidectomy [ ]. One hopes that the authors actually used milligram amounts of lithium carbonate rather than the microgram amounts listed in the article.

Metabolism

Lithium therapy in a 17-year-old man with Kleine–Levin syndrome led to remission of the characteristic manifestations, including hyperphagia [ ].

Hematologic

Lithium has beneficial granulocytopoietic effects [ ]. For example, lithium carbonate (800–900 mg/day) effectively corrected neutropenia due to chemotherapy or radiotherapy in over 85% of 100 cancer patients [ ]. The potential benefit and possible risks of using lithium to treat clozapine-induced neutropenia/agranulocytosis have been reviewed [ ].

• A 29-year-old man with agranulocytosis, who could not tolerate granulocyte-colony stimulating factor, had normalization of peripheral granulocyte counts when he took lithium carbonate 800 mg/day [ ].

• A 16-year-old with severe aplastic anemia failed to respond to treatment with glucocorticoids plus an androgen and to antilymphocyte globulin, but had a strikingly positive response to the combination of lithium and an androgen derivative [ ]. Leukopenia and thrombocytopenia recurred 2 months after lithium was withdrawn and responded to reintroduction of the drug.

The potential of lithium to prevent or treat clozapine-induced granulocytopenia has been reviewed [ ]. In a study of 38 patients on clozapine for schizophrenia or schizoaffective disorder, the addition of lithium increased the leukocyte count [ ]. A 20-year-old man with olanzapine-induced neutropenia 5 mg/day was able to tolerate 20 mg/day while taking lithium [ ].

Skin

Lithium succinate is used topically to treat seborrheic dermatitis [ ]. A topical 8% lithium gluconate ointment was more effective than a placebo ointment in treating 129 patients with facial seborrheic dermatitis (complete remission in 29 versus 3.8%) [ ].

Immunologic and infections

Comments on the generally favorable effects of lithium on immune function have been summarized [ ]. The antiviral and neuroprotective properties of lithium were mentioned in a review of the immune system and bipolar disorder [ ]. The potential benefit of lithium in treating AIDS and AIDS-related dementia, owing in part to its cytokine-regulating and neuroprotective effects, has been reviewed [ ]. Genital Herpes simplex infection has responded to lithium [ ].

• Lithium had an antiviral effect in a 44-year-old woman whose psychiatric symptoms did not improve but who had complete suppression of Herpes labialis for 2 years (after a 30-year history of at least twice-yearly episodes) followed by a recurrence, only 5 days after stopping the drug [ ].

Cancers

In one study, there was a lower risk of cancer in both 609 patients taking lithium and 2396 psychiatric controls compared with the general population, and in those taking lithium, there was a non-significant trend toward an even lower risk of non-epithelial tumors [ ].

Lithium gamolenate, a compound with in vitro antitumor activity, given intravenously or orally, was ineffective in treating advanced pancreatic adenocarcinoma (n = 278) [ ]. Adverse reactions attributed to lithium (type unspecified) were reported in two of 93 in the oral group (mean serum lithium 0.15 mmol/l), five of 90 with low-dose intravenous administration (mean serum lithium 0.4 mmol/l), and seven of 95 with the high-dose intravenous administration (mean serum lithium 0.8 mmol/l).

Lithium versus carbamazepine

In a 2-year, double-blind study, lithium was superior to carbamazepine in prophylactic efficacy, although it caused more adverse reactions ( Table 1 ) [ ].

Lithium versus divalproex

In a randomized, placebo-controlled, 12-month maintenance comparison of lithium and divalproex in 372 bipolar I out-patients, neither active drug was more effective than placebo on the primary outcome measure—the time to recurrence of any mood episode [ ]. While a history of intolerance to either lithium or divalproex was an exclusion criterion, it was not stated whether or not prior non-responders were entered and, if so, how many. The following adverse effects were significantly more frequent:

• (a)

  with lithium than with placebo: nausea, diarrhea, and tremor;

• (b)

  with divalproex than with placebo: tremor, weight gain, and alopecia;

• (c)

  with lithium than with divalproex: polyuria, thirst, tachycardia, akathisia, and dry eyes;

• (d)

  with divalproex than with lithium: sedation, infection, and tinnitus.

Unfortunately, all dropouts were pooled, whether due to adverse events or non-compliance, making overall tolerability comparisons impossible.

In an open study of 37 patients aged 5–18 years with a current manic or mixed episode, who were treated for 6 months with either divalproex sodium plus risperidone or lithium plus risperidone, lithium was given in a dose of 10–30 mg/kg/day, beginning with a single dose of 150 mg or 300 mg, and gradually increasing the dose to produce a plasma concentration in the usual target range [ ]. About 80% of patients responded in each group and over 60% of patients “remitted”. Adverse reactions were similar in the two groups over the 6-month treatment period, and included weight gain, sedation, nausea, increased appetite, stomach pain, tremor, and cognitive dulling. Three of 17 patients taking lithium plus risperidone developed polyuria compared with none of those taking divalproex sodium plus risperidone. Two of 20 patients taking divalproex sodium plus risperidone developed galactorrhea compared with none of those taking lithium plus risperidone.

Lithium versus lamotrigine

The role of lamotrigine in the treatment of bipolar disorder has been reviewed, and combination therapy with lamotrigine plus other mood stabilizers, including lithium, has been particularly discussed [ ]. Lamotrigine has a favorable tolerability profile compared with lithium, but lithium has better antimanic effects than lamotrigine, which exerts its antidepressant effects sooner than lithium.

In a subanalysis of two 18-month maintenance studies of the use of lithium, lamotrigine, or placebo in delaying relapse in subjects with type I bipolar illness, 98 subjects 55 years of age or older were identified [ ]. Lithium delayed the time to mania compared with placebo, but lamotrigine also delayed the time to either mania or depression compared with placebo.

Lithium versus olanzapine

In a 12-month relapse prevention comparison of olanzapine and lithium in subjects initially stabilized on the combination, each was efficacious in preventing relapse into either mania or depression [ ]. Olanzapine was significantly better than lithium in preventing relapse into mania or mixed mania, but lithium was better than olanzapine in preventing relapse into depression.

Lithium versus quetiapine

Quetiapine has been approved by the FDA as monotherapy for the treatment of acute mania. Quetiapine has been evaluated in combination with lithium or divalproex in 191 patients who had been recently manic [ ]. After treatment with quetiapine plus lithium or divalproex for 7–28 days, the patients were randomized to either additional quetiapine or placebo and followed for 3 weeks more. Early discontinuation was more frequent in the placebo group than in the quetiapine group. The intention-to-treat population included 81 taking quetiapine and 89 taking placebo. The mean dose during the last week in patients taking quetiapine was 504 mg/day. Patients taking quetiapine had a greater improvement in their Young Mania Rating Scale score (YMRS) than patients taking placebo. The response rate (50% or greater improvement from baseline using the YMRS) was significantly higher in the group with added quetiapine than added placebo. Common adverse events included somnolence, dry mouth, weakness, and postural hypotension. The authors concluded that quetiapine was a useful adjunct to treat mania in combination with standard measures and that it was well tolerated.

In acute non-mixed mania, lithium was significantly more effective than placebo and equivalent to quetiapine in reducing manic symptoms, as measured by the Young Mania Rating Scale [ ]. In addition, a larger fraction of subjects taking lithium or quetiapine remained in the study compared with those taking placebo. The effect was evident in the first week of treatment and was maintained throughout the 3 months of the study.

Lithium versus valproate

In 29 patients, the burden of taking lithium (n = 17) was compared with that of valproate (n = 12) using a visual analogue scale. Adverse effects were common but not significantly different between drugs [ ], a finding that contrasts with the common impression that valproate is better tolerated. Indeed, a telephone interview of 11 adolescents taking lithium and 32 taking valproate found more adverse effects, poorer compliance, and greater perceived burden in the lithium group. There was a non-significant trend toward more weight gain with valproate (mean 12 kg) than with lithium (mean 9 kg) [ ].

Lithium versus valproate and divalproex

Lithium plus risperidone (n = 33) has been compared with valproate plus risperidone (n = 46) in the acute and continuation treatment of mania [ ]. Both groups were initially studied during a bout of mania, and both groups improved without a significant difference in response rate between the two groups. At week 12, 88% of the patients taking lithium plus risperidone and 80% of those taking valproate plus risperidone were in remission. There were no differences in adverse reactions. The major findings of this study suggested that risperidone could be combined with either lithium or valproate and that efficacy was similar, independent of which mood stabilizer was used. The dose of risperidone was 0.5–6.0 mg/day, with a mean of 1.7 mg/day in the lithium group and 2.2 mg/day in the valproate group.

The Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation (BALANCE) Study is now under way. It involves combination therapy with either lithium 400 mg/day plus valproate 500 mg/day or double those doses and then randomization to double-blind treatment with lithium plus valproate placebo, lithium plus valproate, or valproate plus lithium placebo. The study involves patients with bipolar I affective disorder who require maintenance treatment, and the randomization phase is scheduled to last 2 years, with the initial intention of randomizing 3000 patients. The start-up phase, which was designed to refine the trial design and procedures, has been reported as a pilot study in 30 patients [ ]. The main findings were that the combination of lithium plus valproate was tolerable and the results suggested that an initial open design would enhance patient flow. Also, the targeted sample size was revised to about 1068 patients based on the data from the pilot study.

In relapse prevention studies, valproate was superior to lithium in the prevention of recurrences over 1 year in subjects who initially presented with a dysphoric manic episode [ ].

However, lithium was equivalent to divalproex in the prevention of relapse in rapid cycling subjects over 20 months [ ]. It was also equivalent to divalproex in youths aged 5–17 years with type I or II bipolar illness, randomly assigned to either agent and followed for 76 weeks [ ].

Lithium versus psychotherapy

Psychodynamic supportive psychotherapy (n = 107) has been compared with psychotherapy plus medication (n = 101) in patients with major depressive disorder [ ]. The medications included venlafaxine, selective serotonin reuptake inhibitors, nortriptyline, and nortriptyline plus lithium. Lithium was used as an augmentation strategy in the patients who took lithium and nortriptyline (number not given). There were no differences in outcomes between the two treatment groups. No adverse reactions specific to lithium were reported.

Blood pressure

There is a higher mortality from cardiovascular diseases among patients with bipolar affective disorder than in the general population. Of 81 patients taking lithium monotherapy, 40 were studied in detail; one had hypothyroidism and six had hypertension [ ]. Of the 81 patients 13 were taking antihypertensive drugs, suggesting a high prevalence of hypertension. One of the points of the study was to assess if lithium was a factor in cardiovascular risk in these patients, but there was no correlation between the duration of lithium treatment or the duration of bipolar disorder and the presence of hypertension.

Two patients who were taking lithium carbonate for mood disorders and who underwent coronary artery bypass grafting developed refractory hypotension during cardiac surgery, which responded to methylthioninium chloride [ ]. The authors suspected that chronic lithium therapy had caused cardiac embarrassment and recommended that lithium be withdrawn before cardiac surgery.

Cardiac dysrhythmias

In 30 patients there were only minimal electrocardiographic changes during long-term treatment with lithium using the method of body surface electrocardiographic mapping [ ]. In contrast, a tricyclic antidepressant showed dose-related effects. Non-specific, benign ST-T wave electrocardiographic changes are the most common cardiovascular effects of lithium.

• A 13-year-old boy taking lithium developed a “pseudo-myocardial infarct pattern” on the electrocardiogram; this may have been an overinterpretation of non-specific T-wave changes [ ].

A very uncommon adverse effect involves sinus node dysfunction (extreme bradycardia, sinus arrest, sinoatrial block), which can be associated with syncopal episodes, perhaps due to hypothyroidism [ , ]. In such cases, lithium must either be withdrawn or continued in the presence of a pacemaker. At therapeutic concentrations, other cardiac conduction disturbances have been reported, sometimes in conjunction with hypercalcemia [ ], but are uncommon.

Two reviews of the cardiac effects of psychotropic drugs briefly mentioned lithium and dysrhythmias, with a focus on sinus node dysfunction [ , ], reports of which, as manifested by bradycardia, sinoatrial block, and sinus arrest, continue to accumulate in association with both toxic [ ] and therapeutic [ , ] serum lithium concentrations. The rhythm disturbance normalized in some cases when lithium was stopped [ , ], persisted despite discontinuation [ ], or was treated with a permanent cardiac pacemaker [ ]. Of historical interest is the observation that the first patient treated with lithium by Cade developed manifestations of toxicity in 1950, including bradycardia [ , ].

There have been several reports of bradycardia and sinus node dysfunction.

• During an episode of lithium toxicity (serum concentration 3.86 mmol/l), a 42-year-old woman developed sinus bradycardia that required a temporary pacemaker [ ]. There was marked prolongation of sinus node recovery time. Lithium was withdrawn and the patient underwent hemodialysis once daily for 3 days; sinus node recovery time normalized. The presence of nontoxic concentrations of carbamazepine may have contributed to the condition.

• A 65-year-old man taking lithium for 2 years, with therapeutic concentrations, developed sinus bradycardia (30/minute), which remitted when the drug was stopped and recurred when it was restarted [ ]. Implantation of a permanent pacemaker allowed lithium to be continued.

• Asymptomatic bradycardia occurred in three of 15 patients treated for mania with a 20 mg/kg oral loading dose of slow-release lithium carbonate [ ].

• A 9-year-old boy whose serum lithium concentration was 1.29 mmol/l had a sinus bradycardia with a junctional escape rhythm (40 beats/minute), which normalized at a lower lithium concentration [ ].

• A 58-year-old woman with lithium toxicity developed an irregular bradycardia (as low as 20 beats/minute), which resolved during hemodialysis; persistent sinoatrial conduction delay suggested that she was predisposed to the bradydysrhythmia [ ].

• A 52-year-old man took an overdose of lithium (serum concentration 4.58 mmol/l) and developed asymptomatic sinus bradycardia with sinus node dysfunction and multiple atrial extra beats, which resolved after hemodialysis [ ].

• A 66-year-old woman with pre-existing first-degree AV block, developed sinus bradycardia, a junctional rhythm, a prolonged QT interval, and syncopal episodes (serum lithium concentration 1.4 mmol/l in a 40-hours sample) about 2 weeks after beginning lithium therapy. She was treated successfully with a pacemaker and a lower dose of lithium [ ].

• A 36-year-old man became hypomanic after lithium was withdrawn because of symptomatic first-degree atrioventricular block (although, how first-degree block could have caused symptoms is unclear) [ ].

• A 44-year-old woman developed atropine-resistant but isoprenaline-sensitive bradycardia (36 beats/minute), thought to be due to sinus node dysfunction related to lithium, fentanyl, and propofol [ ].

• A 52-year-old man with a serum lithium concentration of 4.58 mmol/l had sinus node dysfunction with multiple atrial extra beats and an intraventricular conduction delay, which normalized following hemodialysis [ ]. Two patients, a 58-year-old woman and a 74-year-old woman, developed sick sinus syndrome while taking lithium but were able to continue taking it after pacemaker implantation [ , ].

• A 59-year-old woman with syncope and sick sinus syndrome, which remitted when lithium was withdrawn, recurred when lithium was restarted, and then persisted despite lithium withdrawal; after a pacemaker was implanted she was treated successfully with lithium for 7 years [ ].

Lithium can also occasionally cause tachycardia.

• A 59-year-old man was noted to have tachycardia, a shortened QT interval, and nonspecific ST-T changes, while hospitalized with lithium-associated hypercalcemia [ ].

An extension of a previously published study [ ] added a third comparator group of 18 hypercalcemic non-lithium treated patients and compared them with 12 hypercalcemic lithium patients, 40 normocalcemic lithium patients, and 20 normocalcemic bipolar patients taking anticonvulsant mood stabilizers [ ]. Both hypercalcemic groups had more conduction abnormalities than the other two groups, but did not differ from each other in this regard. While the authors concluded that both lithium and calcium played important roles in the dysrhythmias, their data suggested that hypercalcemia alone was the critical factor.

Cardiac dysrhythmias associated with lithium intoxication in the elderly included sinus node dysfunction and junctional bradycardia [ ]. A retrospective chart review of patients on lithium who had mild but persistent hypercalcemia (n = 12) showed a greater frequency of cardiographic conduction disturbances compared with normocalcemic patients taking lithium (n = 40) and normocalcemic bipolar patients taking anticonvulsant mood stabilizers (n = 20), although the overall frequency of cardiographic abnormalities did not differ significantly among the groups [ ]. When 21 patients without cardiovascular disease (mean serum lithium 0.66 mmol/l) were compared with healthy controls using standard electrocardiography, vector cardiography, and electrocardiographic body surface potential mapping, the only abnormality was a reduction in the initial phase of depolarization, a finding of questionable clinical significance [ ].

Abnormalities of the QT interval have been explored in 495 psychiatric patients (87 taking lithium, but many of them also taking other drugs) and 101 healthy controls [ ]. There was no association of lithium with QT _c prolongation but it was associated with nonspecific T-wave abnormalities (odds ratio 1.9) and increased QT dispersion (odds ratio 2.9). Caution was suggested if lithium is used with drugs associated with QT _c prolongation, such as tricyclic antidepressants, droperidol, and thioridazine.

Sudden death has been reported in 14 psychiatric patients and the literature has been reviewed regarding occult cardiac problems, psychotropic drugs, and sudden death [ ].

• A 57-year-old man with bipolar disorder taking olanzapine, lithium, and other drugs had underlying mitral valve prolapse, left ventricular hypertrophy, and His bundle anomalies; he died suddenly, probably because of a cardiac dysrhythmia.

The authors suggested that cardiac pathology should be systematically evaluated in patients who take psychotropic drugs.

Cases of lithium toxicity, its cardiac effects, and issues of cardiac dysfunction in children have been reviewed in the light of a cardiac dysrhythmia in a child.

• A 10-year-old boy developed abdominal pain, diarrhea, and vomiting over 2 days [ ]. He had a history of bipolar disorder, with psychotic features, a schizoaffective disorder, an intermittent explosive disorder, and attention deficit hyperactivity disorder. He had several other medical problems, including hypothyroidism, asthma, and seizures. He was taking many drugs, including methylphenidate, escitalopram, oxcarbazepine, clonidine, Depakote, thyroid hormone, and lithium. The serum lithium concentration was 3.1 mmol/l. Electrocardiography showed a broad-complex tachydysrhythmia, which persisted despite treatment with intravenous adenosine and lidocaine. The cardiac rhythm was interpreted as a ventricular tachycardia. He was given intravenous procainamide, resulting in temporary slowing of his cardiac rhythm, and a continuous procainamide infusion produced stable sinus rhythm. Over the next 36 hours, he continued to have treatment for his lithium toxicity and procainamide for his ventricular dysrhythmia, and improved. At follow-up a 24-hour Holter monitor showed first-degree atrioventricular block.

The diagnosis in this patient is unclear. He obviously had a severe behavioral disturbance, which required treatment; however, it is not clear if his polypharmacy was appropriate for his condition.

In two studies lithium treatment was associated with prolongation of the corrected QT interval (QT _c ). A retrospective analysis of the records of 76 patients taking lithium showed that intervals of over 440 msec were significantly more common in subjects with lithium concentrations over 1.2 mmol/l than in those with concentrations in the usual target range (55% versus 8%); T wave inversion was also more common in subjects with high lithium concentrations (73% versus 17%) [ ].

Similar results have been reported in 39 in-patients with either bipolar illness or schizophrenia; the duration of the QT _c interval correlated significantly with lithium concentrations and those with the longest QT _c intervals had the highest lithium concentrations [ ].

Cardiomyopathies

A study of cardiomyopathies found a specific cause in 614 of 1230 patients (the remainder were diagnosed as idiopathic). One was attributed to lithium but no details were provided [ ].

In a study of 1230 patients with initially unexplained cardiomyopathies, lithium was implicated in one case [ ]. Using a data-based mining Bayesian statistical approach to the WHO database of adverse reactions to examine antipsychotic drugs and heart muscle disorders, a significant association was found between lithium and cardiomyopathy, but not myocarditis [ ]. The authors acknowledged that further study is needed to determine if the association is causal.

• A 78-year-old woman developed a cardiomyopathy while taking lithium, imipramine, amineptine, levomepromazine, and lorazepam; it resolved when the medications were withdrawn [ ]. Whether lithium was causally involved is not known.

Cerebellar syndromes

Chronic neurological sequelae of intoxication included two patients with a persistent cerebellar syndrome and severe cerebellar atrophy [ ], one with subcortical dementia [ ], and one with a diffuse sensorimotor peripheral neuropathy [ ].

• An 86-year-old man with a serum lithium concentration of 0.7 mmol/l presented with a several month history of asterixis which resolved fully within 2 weeks of stopping lithium [ ].

• Symptoms suggestive of toxicity at therapeutic serum concentrations also occurred in a 49-year-old man taking lithium (0.7 mmol/l), carbamazepine, and trifluperidol, who developed persistent cerebellar deterioration during a febrile episode of lobar pneumonia [ ].

• Another patient who developed cerebellar symptoms consistent with lithium neurotoxicity despite a low therapeutic serum concentration (0.5 mmol/l) was more fortunate, as the symptoms resolved promptly when lithium was withdrawn [ ].

• Permanent cerebellar sequelae occurred in a 36-year-old man after intoxication at therapeutic lithium concentrations [ ].

A literature review of permanent neurological complications of acute lithium toxicity noted that a cerebellar syndrome is quite common and that neuroleptic drugs can worsen toxicity, as might rapid reduction of raised serum lithium concentrations [ ]. However, the latter point is speculative at best; hemodialysis remains the treatment of choice for severe lithium poisoning.

In a review of published cases of the syndrome of irreversible lithium-induced neurotoxicity (SILENT), cerebellar dysfunction was the most commonly reported long-lived outcome [ ].

Convulsions

A proconvulsive effect of lithium was also suggested in two patients purported to have temporal lobe epilepsy, who improved when carbamazepine replaced lithium [ ]. Twelve cases of status dystonicus of varying causes included a woman with post-traumatic dystonia, who was treated unsuccessfully with lithium. Despite the lack of response, her muscular spasms worsened when lithium was stopped [ ].

Five patients taking lithium for unspecified durations developed multifocal action myoclonus without reflex activation, which resolved fully when the drug was withdrawn [ ].

• A patient presented with non-convulsive status epilepticus and a serum lithium concentration of 1.9 mmol/l [ ].

• A prolonged seizure occurred after electroconvulsive therapy (ECT) in a 45-year-old man taking lithium, bupropion, and venlafaxine [ ].

Creutzfeldt–Jakob-like syndrome

A reversible Creutzfeldt–Jakob-like syndrome has been described in patients taking lithium.

• A 65-year-old woman taking lithium, levomepromazine, and phenobarbital developed a Creutzfeldt–Jakob-like syndrome after she had mistakenly increased her lithium dosage [ ].

• A 66-year-old man presented comatose with an EEG suggestive of Creutzfeldt–Jakob encephalopathy after an 11-month history of progressive dementia and parkinsonism [ ]. Lithium (serum concentration 1.3 mmol/l), which he had been taking for 13 years, was withdrawn, and by day 78, clinical examination showed only mild neurological impairment.

Lithium can cause confusional states as well as myoclonic jerks [ ]. Consequently, confusing lithium-induced encephalopathy with Creutzfeld–Jakob disease is understandable [ ].

Parkinsonism

Occasionally, long-term use of lithium is associated with cogwheel rigidity and a parkinsonian tremor [ , ]. More often than not, concurrent or past treatment with an antipsychotic drug is involved. In a review of SSRI-induced extrapyramidal adverse effects, lithium was listed, but not discussed, as a possible risk factor [ ]. A review of drug-induced parkinsonism provided references to case reports of lithium’s “occasionally inducing or exacerbating parkinsonism” [ ].

Two patients developed parkinsonism after taking lithium for many years, but did not improve when the drug was withdrawn and a causal relation could not be established [ ].

Dystonias

Reversible tardive dystonia has been attributed to lithium [ ].

Neuroleptic malignant syndrome

Whether lithium alone can cause neuroleptic malignant syndrome is controversial. There have been reports of neuroleptic malignant syndrome in patients taking lithium and a neuroleptic drug [ ], as in the following cases:

• A 39-year-old woman who had overdosed with lithium and who took a single dose of haloperidol [ ].

• A 63-year-old man taking lithium and amoxapine [ ].

• A 23-year-old woman taking lithium, olanzapine, and fluoxetine [ ].

• A 45-year-old man took an intentional overdose of lithium [ ]. He was dialysed and stabilized, but on day 10 developed neuroleptic malignant syndrome. He died after developing acute renal insufficiency and acute respiratory distress syndrome.

• Neuroleptic malignant syndrome occurred in a 47-year-old man taking lithium and valproate who had ziprasidone added [ ].

However, a case–control study (n = 12 with the syndrome, n = 24 controls) found no such association [ ], but since none of the patients with neuroleptic malignant syndrome was taking lithium, little can be concluded from such a finding.

Headache

• A 64-year-old woman had a 2-week history of daily bilateral holocranial headache as the presenting complaint of lithium toxicity (serum concentration 2.5 mmol/l); dosage reduction resolved the headache and the extrapyramidal and cerebellar effects [ ].

Myasthenia

Since lithium interferes with intracellular calcium mobilization and can weaken muscular activity, it can unmask myasthenia gravis [ ].

• A 51-year-old man developed a myasthenic syndrome which resolved when lithium was withdrawn [ ]. The authors referred to three other previously reported cases of lithium-induced myasthenia.

Pseudotumor cerebri

Pseudotumor cerebri (benign intracranial hypertension) has been linked to lithium in over 30 cases, with headache, papilledema, increased intracranial pressure, reduced vision, and a risk of blindness [ ]. The condition tends to improve on withdrawal, but surgical intervention may sometimes be necessary. A review of pseudotumor cerebri devoted one paragraph to induction of this condition by lithium and provided six references but no new information [ ].

• A 17-year-old woman developed pseudotumor cerebri with headache after she had taken lithium for 6.5 weeks [ ]. Papilledema and increased intracranial pressure resolved fully when lithium was withdrawn, and she was given acetazolamide.

Serotonin syndrome

Serotonin syndrome has been reviewed twice, but mention of lithium as a possible contributing factor was scanty [ , ].

Somnambulism

After almost a two-decade nap, interest in lithium-induced somnambulism was reawakened by a questionnaire survey of 389 clinic patients that found sleepwalking in 6.9% of those taking lithium alone or with other drugs compared with a 2.5% prevalence in the general population [ ].

• A 52-year-old man had a 5-year history of sleepwalking 2–3 times a week beginning 3 months after starting lithium [ ]. On one occasion, he was injured in a fall when sleepwalking through a second-story window. When lithium was stopped for 3 months, the problem resolved only to recur when it was restarted.

Stuttering

Stuttering worsened in a 48-year-old man while he was taking lithium, with improvement when he was switched to valproate [ ].

Tremor

Lithium commonly causes a benign postural tremor, especially early in the course of treatment [ ] and can enhance physiological tremor [ ]. Susceptibility factors include higher serum lithium concentrations, a family history of tremor, high caffeine intake, and the use of other drugs that cause tremor (for example antidepressants, valproate). The tremor is often well tolerated, but in some cases, it can be socially or occupationally problematic. In such cases, treatment possibilities include reducing the dose of lithium, the use of a modified-release formulation, reducing caffeine intake, or the addition of a tremor-reducing drug, such as a beta-blocker [ ], primidone [ ], or possibly gabapentin [ ].

Tremor was reported as an adverse effect of lithium in 12 of 22 men and 10 of 38 women who had taken it for at least 1 year [ ]. In an open study, there was full remission of lithium tremor in four of five patients treated with vitamin B ₆ [ ].

A double-blind study in which 31 patients with breakthrough depression taking lithium received augmentation with either paroxetine or amitriptyline and showed a quantitative increase in tremor activity with combined therapy, but no significant change in tremor frequency [ ].

In 10 psychiatric inpatients with asterixis the drugs most often used were clozapine (n = 8), lithium (n = 7), and carbamazepine (n = 7) [ ].

Vision

Lithium can alter retinal sensitivity to light, and concern has been expressed that bright light therapy for seasonal mood disorder can increase the risk of photoreceptor cell damage, although such concerns have not been confirmed clinically [ , ].

Optic neuritis associated with lithium toxicity [ ] may not have been caused by lithium.

Other effects on the visual system attributed to lithium include reduced accommodation, exophthalmos, extraocular muscle abnormalities, nystagmus (most characteristically downbeat), oscillopsia, photophobia, and papilledema with visual impairment (pseudotumor cerebri) [ ].

• A 21-year-old woman developed temporary blindness possibly related to lithium toxicity [ ].

Hearing

The finding of reversible lithium-induced moderate hearing loss (especially low frequency) in guinea pigs has led to speculation that similar findings could occur in humans [ ].

Cognitive effects

All mood stabilizers can cause cognitive dysfunction. In a comparative study of commonly used mood stabilizers lithium caused cognitive problems that were greater than lamotrigine and olanzapine, but less than topiramate, valproate, and carbamazepine [ ].

Most people taking lithium have no complaints about its effects on mental processes; they feel normal and function normally. Mild cognitive effects can occur, although it is sometimes difficult to determine whether they are due to the lithium, the resolution of manic euphoria, the presence of mild depression or hypothyroidism, or the effects of other medications. Complaints can include reduced reactivity, lack of spontaneity, loss of emotional tone, and patchy memory impairment. Lithium reportedly has adverse effects on memory, speed of information processing, and reaction time [ , ]. It has been suggested that the risk of driving accidents may be increased in patients taking lithium, but there is no evidence that this is so. As with any psychotropic drug, patients should be cautious about driving or operating dangerous machinery until they know how they will react to lithium. These mild cognitive adverse reactions can be underappreciated by clinicians, yet be a cause of non-adherence to therapy. The action of lithium on the hypothalamic–pituitary–thyroid axis has been discussed in relation to its cognitive effects [ ]. Although, the English abstract of a Polish review concluded that there is no evidence of significant cognitive deficits caused by lithium [ ], others dispute this conclusion [ ].

Assessment of cognitive performance in 43 patients with bipolar I disorder showed no correlation between the use of lithium, carbamazepine, or valproate, and full-scale IQ or general and working memory (all of which were impaired by antipsychotic drugs) [ ]. While a deficit in sustained attention was noted in 19 euthymic patients with bipolar disorder (17 taking medications, 11 taking lithium alone or in combination), there was no difference between those taking and those not taking lithium [ ].

In a 3-week, double-blind study of the cognitive effects of lithium (serum concentration about 0.8 mmol/l; n = 15) versus placebo (n = 15) in healthy subjects, lithium did not impair implicit recall, ability to process two tasks concurrently and simultaneously, short-term memory, or selective attention, but caused impaired learning during repeated administration of memory tests [ ]. Since neuropsychological testing could not distinguish lithium treatment from pre- and post-treatment in the lithium group, any lithium effects must be considered subtle at best.

Lithium has diverse effects on creativity. While creativity can suffer from the absence of mania or from lithium-induced adverse effects, it can also be improved by the mood stabilization that lithium produces, or may be unaffected by treatment [ ].

Four of 17 studies of the cognitive effects of lithium were deemed to have acceptable methods. Reported adverse reactions included effects on memory, speed of information processing, and reaction time (often in the absence of subjective complaints), suggesting that the risk of driving accidents might be increased when patients are taking lithium [ , ]. Interventions for lithium-induced cognitive impairment include dosage reduction, use of a modified-release formulation, treatment of thyroid dysfunction, and assessing the role of concomitant illness and medication. When 67 patients who complained of cognitive deterioration while taking lithium were treated with aniracetam, 97% reported subjective improvement [ ].

Delirium and dementia

In a case–control study, lithium was found to be one of several risk factors for delirium in 91 psychiatric in- patients (odds ratio 2.23), although the authors concluded that this observation may have been confounded by an association with manic episodes [ ].

• A 38-year-old woman who had tolerated lithium for 20 years developed delirium following a manic episode, despite therapeutic concentrations of lithium (0.7–1.0 mmol/l); the episode remitted fully after lithium was withdrawn [ ].

• A 36-year-old developed a febrile confusional state in the absence of infection while taking lithium (serum concentrations 0.37 and 0.58 mmol/l) and cyamemazine, resulting in a persistent cerebellar syndrome [ ].

• A 62-year-old woman became delirious when lithium at therapeutic concentrations was added to valproate, haloperidol, and biperiden [ ]. The delirium resolved after all drugs were withdrawn, but 6 months later she still had choreoathetoid movements.

The incidence of delirium in elderly subjects (over 65 years old) taking lithium does not appear to be higher than in those who are taking valproate [ ]. Among 5360 subjects with a mood disorder who had taken lithium or valproate in the previous year, the incidence of delirium with valproate was very similar to that of lithium (4.1 versus 2.8 cases/100 person years; HR = 1.36; 95% CI = 0.94, 1.97). Both of these rates were significantly lower than the rates observed with the anticholinergic drug benzatropine.

Actually, lithium has been associated with many effects that are believed to be neuroprotective [ ]. Most importantly, it reduces the activity of glycogen synthase kinase-3 (GSK-3), which leads to reduced production of the tau protein [ , ]. However, lithium may actually increase the production of amyloid beta [ ], although previous reports have suggested that lithium reduces amyloid beta and its consequent toxicity [ , ].

Clinically, lithium may protect patients against dementia, although it has been reported that patients who take lithium are actually at a higher risk of developing dementia [ ].

Patients with bipolar disorder are at greater risk of dementia as they age. In 114 elderly euthymic bipolar patients, of whom 66 were taking lithium and 48 were not, the prevalence of dementia was 19% compared with 7% in a comparable non-bipolar population [ ]. However, only three of those taking lithium developed dementia, compared with 16 of those who were not. This may be related to the ability of lithium to inhibit glycogen synthase kinase 3 beta (GSK 3beta), which results in reduced phosphorylation of the tau protein in a mouse model of Alzheimer’s disease [ ].

Suicide

In a systematic review of 32 randomized trials in which 1389 patients took lithium and 2069 took another agent (carbamazepine, divalproex, lamotrigine, or the antidepressants amitriptyline, fluvoxamine, mianserin, and maprotiline), among the seven studies that reported suicides, lithium-treated patients had significantly fewer completed events [ ]. These included two suicides on lithium (out of 503, 0.4%) and 11 suicides on other agents (two placebo, two amitriptyline, six carbamazepine, and one lamotrigine, out of a total of 601, 1.8%) (OR = 0.26; 95% CI = 0.09, 0.77).

The lower rate of completed suicides in those taking lithium is of particular note, since suicidal ideation may actually be more common in lithium-treated patients. In 128 patients followed prospectively for an average of 13 years suicidal ideation was non-significantly higher in lithium-treated patients than in those taking valproate or carbamazepine [ ]. This may be related to clinician preference, since among patients with bipolar affective disorder and suicidal ideation in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) clinicians were more likely to prescribe antidepressants and second-generation antipsychotic drugs, while they reserved lithium for more severely ill individuals [ ].

There was a similar pattern in an observational study of all lithium prescriptions and recorded suicides in Demark from 1995 to1999 inclusive [ ]. Purchasing lithium was associated with a higher rate of suicide, but purchasing lithium at least twice was associated with a significantly lower risk (0.44; 95% CI = 0.28, 0.70). In other words, lithium is prescribed for patients who are at high risk of suicide, but continuing to take lithium appears to be protective. These studies have laid the foundations for a current adequately powered, prospective study of the purported anti-suicide effect of lithium [ ].

Additional data have emerged that suggest that lithium reduces suicide risk. A meta-analysis of 31 available studies comprising some 85 229 person years showed that the risk of completed suicide was nearly 5 times lower in lithium-treated patients (RR = 4.91; 95% CI = 3.82, 6.31) [ ]. Additionally, an analysis of suicides in 8 studies comprising 2434 person years in 329 patients with major depression showed a significant reduction with lithium (RR = 6.77; 95% CI = 2.10, 77) [ ].

Corticotropin (ACTH)

Calcium infusion in lithium patients (n = 7) and controls (n = 7) caused similar increases in ACTH concentrations across a physiological range of calcium [ ].

Prolactin

Serum prolactin concentrations in patients taking long-term (n = 15) or short-term (n = 15) lithium did not differ from controls [ ]. In another study, when compared with 17 healthy controls, 20 euthymic bipolar patients who had taken lithium for more than 6 months had significantly lower serum prolactin concentrations (9.72 ng/ml versus 15.56 ng/ml), but prolactin concentrations in short-term lithium users (n = 15) did not differ from controls [ ]. Antipsychotic drugs were not involved.

Diabetes insipidus

Two of ten patients taking long-term lithium therapy were thought to have hypothalamic diabetes insipidus, because of a positive response to desmopressin [ ].

For nephrogenic diabetes insipidus, see under Urinary tract below.

Hypothalamic–pituitary–adrenal axis

Hypothalamic–pituitary–adrenal axis function in bipolar disorder has been reviewed, but lithium was mentioned only in passing [ ]. Two studies (n = 25, n = 24), possibly reporting many of the same patients, showed that lithium augmentation of antidepressant-resistant unipolar depression increased hypothalamic–pituitary–adrenal axis activity, measured by the dexamethasone suppression test, either alone or combined with the corticotropin releasing hormone test [ , ]. However, the tests did not distinguish between lithium responders and non-responders.

Thyroid

Both lithium and mood disorders are associated with a wide range of thyroid abnormalities [ ]. However, thyroid disease itself is not particularly common. In an epidemiological study of thyroid disease in over half a million people in Denmark for 4 years (2 027 208 person years) there were only 685 cases of new-onset hypothyroidism; lithium was associated with only a small fraction of those cases (1.6%) [ ]. These high rates of increases in TSH increase the risk of thyroid cancer, and thyroid papillary carcinoma has been reported in a patient taking long-term lithium [ ].

The many effects of lithium on thyroid physiology and on the hypothalamic–pituitary axis and their clinical impact (goiter, hypothyroidism, and hyperthyroidism) have been reviewed [ ]. Lithium has a variety of effects on the hypothalamic–pituitary–thyroid axis, but it predominantly inhibits the release of thyroid hormone. It can also block the action of thyroid stimulating hormone (TSH) and enhance the peripheral degradation of thyroxine. Most patients have enough thyroid reserve to remain euthyroid during treatment, although some initially have modest rises in serum TSH that normalize over time.

Both goiter and hypothyroidism continue to be reported as complications of lithium therapy [ , ].

Of 42 bipolar patients who had taken lithium for 4–156 months, three had subclinical hypothyroidism, three had subclinical hyperthyroidism, and one was overtly hyperthyroid [ ]. Ultrasonography showed that goiter was present in 38% and mild thyroid dysfunction was suggested in 48% because of an apparent increased conversion of free T4 to free T3. There was no correlation between the duration of lithium therapy and thyroid abnormalities.

In a cross-sectional study of 121 patients taking lithium, there was no difference in thyroid function tests among those taking treatment for 0.7–6 months, 7–10 months, or 61–240 months. However, when compared with healthy volunteers (n = 24) and prelithium controls (n = 11), there was a significant increase in radioiodine uptake in all lithium groups. Serum TSH concentrations were higher in prelithium patients than controls and highest in those taking lithium. Being from an iodine-deficient area appeared to predispose lithium patients to abnormally high TSH values and clinical hypothyroidism [ ].

In 1989, in 150 patients at different stages of lithium therapy, thyroid function was assessed and subsequently 118 were reassessed at least once and 54 completed a 10-year follow-up [ ]. The annual rates of new cases of thyroid dysfunction were subclinical hypothyroidism 1.7%, goiter 2.1%, and autoimmunity 1.4%. While these figures were little different from those found in the general population, the authors acknowledged that lithium was a potential cause of thyroid dysfunction.

In a controlled, cross-sectional comparison of 100 patients with mood disturbance who had taken lithium for at least 6 months and 100 psychiatrically normal controls, lithium did not increase the prevalence of thyroid autoimmunity; a minimally larger number of control subjects had antithyroid peroxidase antibodies (11 controls versus 7 patients with mood disorders) and anti-thyroglobulin antibodies (15 versus 8) [ ].

Hypothyroidism

Lithium-induced hypothyroidism has been briefly reviewed [ ]. Some patients develop more persistent subclinical hypothyroidism (TSH over 5 mU/l, free thyroxine normal) and others overt hypothyroidism (higher risk in women, in those with pre-existing thyroid dysfunction, and those with a family history of hypothyroidism). Since subclinical hypothyroidism is not necessarily asymptomatic, treatment with thyroxine may be necessary in this group [ ], as well as in those with more obvious hypothyroidism [ ].

In a review of lithium-induced subclinical hypothyroidism (TSH over 5 mU/l, free thyroxine normal), a prevalence of up to 23% in lithium patients was contrasted with up to 10% in the general population [ ]. It was stressed that subclinical hypothyroidism from any cause can be associated with subtle neuropsychiatric symptoms, such as depression, impaired memory and concentration, and mental slowing and lethargy, as well as with other somatic symptoms. Management guidelines were discussed.

The prevalence of thyroperoxidase antibodies was higher in 226 bipolar patients (28%) than in population- and psychiatric-control groups (3–18%). While there was no association with lithium exposure, the presence of antibodies increased the risk of lithium-induced hypothyroidism [ ].

In 1705 patients, aged 65 years or over, who had recently started to take lithium, identified from the 1.3 million adults in Ontario receiving universal health care coverage, the rate of treatment with thyroxine was 5.65 per 100 person-years, significantly higher than the rate of 2.70/100 person-years found in 2406 new users of valproate [ ]. Of 46 adults taking lithium in a psychiatric clinic, 17% developed overt hypothyroidism while 35% had subclinical hypothyroidism (raised concentrations of thyroid stimulating hormone, TSH) [ ].

Thyroid function tests in 101 lithium maintenance patients were compared with their baseline values and with results in 82 controls without psychiatric or endocrine diagnoses. With hypothyroidism defined as a serum TSH above the reference range, 8 patients were hypothyroid at baseline, and another 40 became so during treatment. Women over 60 years of age were at slightly higher risk and had higher TSH values. Patients with a positive family history of hypothyroidism had raised TSH concentrations sooner after starting lithium (3.7 versus 8.7 years). Whether any patients became clinically hypothyroid was not noted (it was stated that those with grade II hypothyroidism were almost free of symptoms) [ ].

Serum TSH concentrations were raised (10 mU/l or more) in 13 of 61 children aged 5–17 years taking lithium and valproate for up to 20 weeks [ ].

An abstract reported that 23% of 61 children and adolescents taking lithium and divalproex sodium for up to 20 weeks had a TSH concentration over 10 mU/l (reference range 0.2–6.0); however, no clinical information was provided [ ]. Another abstract reported that the prevalence of thyroperoxidase antibodies was higher in bipolar outpatients (28% of 226) than in psychiatric inpatients with any diagnosis (10% of 2782) or healthy controls (14% of 225), but this was not related to lithium exposure; on the other hand, hypothyroidism was associated with lithium exposure, especially in the presence of antithyroid antibodies [ ].

When 22 men and 38 women who had taken lithium for at least a year (mean 6.9 years) for bipolar disorder were evaluated for adverse effects, hypothyroidism requiring thyroid supplementation was found in 16 (14 women and 2 men); 9 had a goiter [ ]. The area from which some of the patients came was known to have a high background incidence of thyroid dysfunction.

The observation that Canada, with ample nutritional iodine, has a relatively high rate of lithium-related hypothyroidism compared with relatively low rates in iodine-deficient countries such as Italy, Spain, and Germany led to the suggestion that ambient iodine may play a role in the genesis of this condition [ ]. This is reminiscent of the association of amiodarone with hypothyroidism or hyperthyroidism in iodine-replete and iodine-deficient areas respectively [ ].

Case reports of adverse thyroid effects of lithium have included the following:

• A 56-year-old man taking lithium whose TSH concentration was abnormally high (50 mU/l) [ ].

• A 44-year-old woman who had taken lithium for 10 years and who developed swelling of the right lobe of the thyroid and hypothyroidism [ ].

• A 63-year-old woman taking long-term lithium who developed subclinical hypothyroidism and primary hyperparathyroidism [ ].

Hyperthyroidism

Despite the predominantly antithyroid effects of lithium, thyrotoxicosis continues to be described during treatment and after withdrawal [ ]. In a retrospective review of 201 patients taking lithium (mean duration 6.4 years), hypothyroidism requiring supplemental thyroxine developed in 10% (3.4% of men, 15% of women) after a mean duration of 56 months. Women over 50 years of age tended to have an earlier onset. Two patients developed goiter requiring surgery and two others developed thyrotoxicosis [ ].

Reports of hyperthyroidism associated with lithium include one in a woman who was also hypercalcemic with a normal parathyroid hormone (PTH) concentration [ ] and two discovered while treating lithium toxicity [ ].

• A 52-year-old woman became thyrotoxic 2 months after stopping long-term lithium therapy; the authors briefly reviewed 10 previous reports [ ].

• A woman with lithium-associated hyperthyroidism lost 2 kg over 3 months, suggesting that lithium may have indirectly caused the weight loss [ ].

Thyroiditis

A retrospective record review of 300 patients with Graves’ disease and 100 with silent thyroiditis who had undergone thyroid scans showed that the likelihood of lithium exposure was 4.7 times higher in the latter, suggesting a link between lithium and thyrotoxicosis caused by silent thyroiditis [ ].

• A 30-year-old man, who had taken lithium for 16 years for bipolar disorder and long-term ciclosporin and prednisolone after a bone-marrow transplant, developed subacute thyroiditis associated with a diffusely enlarged gland that showed heterogeneous echogenicity, but without a clear relation to lithium [ ].

Goiter

Euthyroid or hypothyroid goiter can also complicate lithium therapy, although the goiter is seldom of clinical importance and tends to resolve on withdrawal or with thyroxine treatment. In one ultrasound study, there was a 44% incidence of goiter in patients who had taken lithium for 1–5 years compared with 16% in a control group; cigarette smoking was associated with a greater size and frequency of goiter in both groups [ ].

Hyperthyroidism has also been associated with lithium use and withdrawal, although a cause-and-effect relation has been more difficult to establish. In fact, lithium has been used with some success to treat some forms of hyperthyroidism, particularly in conjunction with propylthiouracil [ ] and ¹³¹ I [ ].

Parathyroid and calcium

Because lithium reduces the intracellular calcium signal, it is occasionally associated with increases in parathyroid hormone (PTH).

• A 56-year-old man with bipolar illness who had taken lithium for 5 years developed an incidental increase in PTH with a concomitant increase in serum calcium; lithium was withdrawn and all the values normalized [ ].

Of 12 patients who underwent parathyroid gland resection while maintaining their lithium intake, only eight remained normocalcemic [ ]. Subclinical increases in PTH probably underlie the observation that lithium was associated with a reduced likelihood of bone fracture in a study of 231 778 bone fractures (OR = 0.75), despite the observation that bipolar illness itself may be related to an increase in bone fractures in subjects not taking lithium (OR = 1.35) [ ].

Lithium toxicity has been reported in a patient with hypercalcemia [ ].

• A 54-year-old man, who had taken lithium for 15 years without problems, suddenly developed food and water aversion, hypercalcemia (2.75 mmol/l), and lithium toxicity, with a serum lithium concentration of 4.3 mmol/l. He was confused, delirious, and irritable. Hemodialysis produced a marked improvement in laboratory tests, which became normal after 9 days.

The authors concluded that the hypercalcemia was due to long-term lithium treatment. The patient’s chief complaint included nausea when he was exposed to food and water, and he therefore refused food and water for 2–3 days before admission. He also had acute renal insufficiency, which was thought to be due to the hypercalcemia, water aversion, and perhaps “idiosyncratic reasons.” The renal insufficiency and water aversion resulted in lithium toxicity. The studies cited in this paper showed that hyperparathyroidism occurs in 5–40% of patients taking long-term lithium, compared with a population frequency of less than 4%, and in a review 27 reports of parathyroid adenoma and 11 of hyperplasia were mentioned [ ]. The hypercalcemia and raised PTH concentrations are often reversible on withdrawal, but surgical intervention may be necessary. So far, long-term lithium therapy has not emerged as a susceptibility factor for reduced bone mineral density or osteoporosis [ ]. In one study, there was a greater frequency of electrocardiographic conduction defects in hypercalcemic patients taking lithium than in normocalcemic patients taking lithium [ ].

Of 15 patients who had taken long-term lithium and who had also had surgery for primary hyperparathyroidism, one had recurrent hyperparathyroidism 2 years after the first operation [ ]. The authors noted that in their experience hyperparathyroidism during lithium treatment was associated with a high incidence of parathyroid adenomas rather than parathyroid gland hyperplasia, and they suggested that lithium might selectively stimulate the growth of parathyroid adenomas in individuals who are susceptible to developing parathyroid adenomas. Furthermore, such adenomas were best treated by excision rather than subtotal parathyroidectomy.

Of 537 patients who had parathyroid glands excised for hyperparathyroidism, 12 (2.2%) had been taking lithium and 11 (2.0%) had been taking it long-term (mean 15.3 years, range 2–30). Manifestations included fatigue, bone pain and fracture, and abdominal pain and constipation. Six had a single adenoma and five had multigland hyperplasia. All resumed lithium, but one had a recurrence after 3 years and one had increased PTH concentrations, but a normal serum calcium. A literature review detected 27 prior reports of parathyroid adenoma and 11 of hyperplasia associated with lithium [ ].

When 15 euthymic bipolar patients who had taken lithium for a mean of 49 months were compared with 10 non-lithium euthymic bipolar controls, the former had significantly higher total serum calcium concentrations and intact PTH (iPTH) concentrations [ ]. The authors advised baseline and periodic serum calcium and iPTH concentrations and bone density measurements in all lithium patients, although whether the benefit outweighs cost is open to question.

Ten patients who had taken lithium for less than 1 year and 13 who had taken it for more than 3 years were assessed for alterations in bone metabolism and parathyroid function [ ]. There were no differences in bone mineral density, serum calcium concentration, or PTH concentration, but both groups had increased bone turnover and the long-term group had non-significantly higher calcium and PTH concentrations (including one hyperparathyroid patient who had an adenoma excised). The authors’ conclusion that lithium therapy is not a risk factor for osteoporosis needs to be tempered by the small sample size, the case of adenoma, and the blood concentration trends.

Total serum calcium and iPTH concentrations were measured in 15 patients taking long-term lithium and 10 lithium-naïve patients; both were significantly higher in the lithium group [ ]. While the number of lithium patients with abnormally high concentrations was not stated, mean iPTH concentrations were almost twice the upper limit of the reference range (102 versus 55 pg/ml).

Parathyroid tumors from nine patients with lithium-associated hyperparathyroidism (six multiglandular, three uniglandular) were compared with 13 non-lithium-associated sporadic parathyroid tumors with regard to gross genomic alterations [ ]. Gross chromosomal alterations were absent in most of the lithium group and were more common in the sporadic group.

In 53 patients studied prospectively at 1, 6, 12, and 24 months, lithium increased serum PTH concentrations (apparent by 6 months) and increased renal reabsorption of calcium in the absence of a significant change in serum calcium [ ]. A prospective study of 101 lithium maintenance patients and 82 healthy controls showed higher serum calcium concentrations during lithium treatment than at baseline or in the controls, and higher calcium serum concentrations in those lithium patients over 60 years of age [ ].

When compared with 12 healthy matched controls, 13 women who had taken lithium for a mean of 8 (range 3–16) years had higher mean ionized and total calcium concentrations, but mean plasma parathormone concentrations did not differ. In eight of the women taking lithium, the calcium concentration was above the upper end of the reference range, and in one the parathormone concentration was abnormally high [ ].

Of 15 patients taking long-term lithium who had surgery for primary hyperparathyroidism, 14 had adenomas (11 single, 3 double) and one had four-gland hyperplasia. All restarted lithium successfully after surgery, except one who again developed hyperparathyroidism, resulting in removal of another adenoma [ ].

Hyperparathyroidism was considered a possible cause of treatment-resistant manic psychosis in a patient taking lithium [ ].

• Hypercalcemia and raised PTH concentrations improved in a woman who had taken lithium for over 20 years after she was switched to divalproex [ ].

• A 64-year-old woman who had taken lithium for over 10 years was admitted with altered consciousness, agitation, and disorientation. The serum calcium was 3.35 mmol/l (reference range 2.1–2.6 mmol/l) and the PTH concentration was raised. With hydration and conversion from lithium to valproate, the serum calcium concentration normalized, but 2 years later disorientation and hypercalcemia recurred and a 150 mg parathyroid adenoma was removed surgically [ ].

• A 53-year-old woman who had taken lithium for 9 years and carbamazepine for 3 years and had a 3-month history of lethargy was found to be hypercalcemic with a raised concentration of iPTH. She was saved from parathyroid surgery when withdrawal of lithium resolved the hypercalcemia [ ].

• A 51-year-old man who had taken lithium for over 10 years presented with nausea, vomiting, anorexia, hypercalcemia (3.1 mmol/l), and increased PTH concentration (iPTH 110 ng/l). Abnormalities resolved after an oxyphilic parathyroid adenoma was excised [ ].

Other reports of hyperparathyroidism in patients taking lithium have included the following:

• A 74-year-old man who had an adenoma resected [ ].

• Two 77-year-old women who developed hyperparathyroidism which was managed medically [ ].

• A 59-year-old man with hypercalcemia and increased PTH concentrations 3 months after starting lithium, which normalized after lithium was withdrawn [ ].

• A 63-year-old woman taking long-term lithium therapy [ ].

• A 39-year-old (sex unspecified) whose adenoma was resected after taking lithium for 10 years [ ].

• Three cases among 26 cases of chronic lithium poisoning [ ].

• A 78-year-old man who had taken lithium for 30 years who presented with dehydration, azotemia, hypernatremia, hypercalcemia, and increased PTH concentrations [ ].

• A woman who had taken lithium for 15 years who became hypercalcemic and stopped taking lithium, but 2 years later had two parathyroid adenomas removed surgically [ ].

• A 42-year-old man who had taken lithium for 17 years and who had raised serum calcium and PTH concentrations which normalized after removal of a parathyroid adenoma [ ].

• Three cases from Denmark [ ] and one from Spain [ ];

• A 78-year-old woman who had taken lithium for 25 years [ ].

• A 59-year-old woman with hyperparathyroidism [ ].

A lithium chloride solution caused changes in gravicurvature, statocyte ultrastructure, and calcium balance in pea root, believed to be due to effects of lithium on the phosphoinositide second messenger system [ ]. The implications with regard to human parathyroid function are obscure.

Diabetes mellitus

Diabetes mellitus is reportedly three times more common in patients with bipolar affective disorder than in the general population [ ]. However, lithium does not appear to increase the risk of diabetes mellitus, and its use in patients with pre-existing diabetes is generally safe, assuming that the diabetes is well controlled.

When lithium toxicity has been reported in patients with diabetes mellitus, it has been attributed to impaired glucose intolerance [ ].

• An increased lithium dosage requirement in a hyperglycemic 40-year-old woman was attributed to the osmotic diuretic effect of glycosuria, increasing lithium excretion [ ].

• Two patients with diabetes mellitus developed lithium toxicity (serum concentrations 3.3 and 3.0 mmol/l) in association with impaired consciousness, and hyperglycemia that resolved after intravenous insulin and fluids [ ].

While the authors of the second report concluded that impaired glucose tolerance had predisposed to lithium intoxication, the opposite is also possible.

Lithium has an insulin-like effect [ ]. Sudden lithium withdrawal was associated with transient diabetes mellitus in a young man with bipolar disorder [ ].

When a 45-year-old man with severe lithium-induced diabetes insipidus developed hyperosmolar, non-ketotic hyperglycemia, it was suggested that poorly controlled diabetes mellitus may have contributed to the polyuria [ ]. Prior contact with a female patient who had developed hyperosmolar coma secondary to lithium-induced diabetes insipidus [ ] allowed physicians 4 years later to treat her safely after a drug overdose and a surgical procedure, by avoiding intravenous replacement fluids with a high dextrose content (despite stopping lithium several years earlier, the patient continued to put out 10 liters of urine daily) [ ].

Difficulty in attaining a therapeutic serum concentration of lithium despite increased doses was attributed to increased renal clearance due to the osmotic effect of glycosuria in a 44-year-old man with poorly controlled diabetes mellitus [ ].

Weight gain

The general perception among clinicians is that lithium causes minimal to moderate weight gain in a similar fashion to quetiapine, risperidone, and valproate [ ]. This is in line with actual observations of long-term changes in weight in subjects randomly assigned to receive lithium (n = 166), lamotrigine (n = 227), or placebo (n = 190) [ ]. After 1 year of lithium treatment, there was an average gain of 2.2 kg, compared with 0.2 kg in placebo-treated subjects, and a loss of 1.2 kg in patients taking lamotrigine. Weight gain was greatest in obese subjects. Non-obese lithium-treated patients gained 1.1 kg after 12 months, which was minimally greater than placebo-treated patients (0.7 kg over 1 year) and lamotrigine-treated subjects (0.5 kg over 1 year). However, obese lithium-treated patients gained 6.1 kg. Lamotrigine-treated obese patients lost 4.2 kg, while placebo-treated obese subjects lost 0.6 kg over 1 year of study follow-up [ ].

Weight gain, a well-recognized adverse reaction to lithium, occurs in one-third to two-thirds of patients [ ]. It is more common in those with prior weight problems and at higher dosages of lithium. Possible mechanisms include complex effects on carbohydrate and lipid metabolism, mood stabilization itself, lithium-induced hypothyroidism, the use of high-calorie beverages to treat lithium-induced polydipsia, and the concomitant use of other weight-gaining drugs (for example valproate, olanzapine, mirtazapine). Recognizing and managing weight gain early in the course of treatment can do much to ensure continued adherence to lithium regimens. Two reviews of weight gain with psychotropic drugs mentioned lithium [ , ].

Risk and magnitude . In a review of psychotropic drug-induced weight gain, the prevalence and magnitude of the problem with lithium was discussed together with risk factors, mechanisms, and management [ ]. Adolescent inpatients treated with risperidone (n = 18) or conventional antipsychotic drugs (n = 19) over 6 months gained more weight than a control group but concomitant treatment with lithium was not a contributing factor [ ].

A review of psychotropic drugs and weight gain included a brief summary of lithium-related weight gain [ ]. A retrospective evaluation of 176 patients taking long-term lithium showed that weight gain was an adverse effect in 18%. While 34% of the total did not adhere to treatment because of somatic adverse reactions, no specific adverse reaction (including weight gain) was associated with non-adherence [ ].

The prevalence of overweight (BMI 25–29) and obesity (BMI 30 or more) was determined in 89 euthyroid bipolar patients and 445 reference subjects [ ]. The rate of obesity in patients taking only lithium was 1.5 times greater than in the reference population (a non-significant difference), compared with a statistically significant 2.5 times greater rate associated with antipsychotic drugs. The bipolar women were more overweight and more obese than the controls and the bipolar men were more obese but not more overweight. Obesity was clearly related to antipsychotic drug use and less so to lithium and anticonvulsants.

A review of the effects of mood stabilizers on weight included a section on lithium in which the authors concluded that lithium-related weight gain occurs in one-third to two-thirds of patients, with a mean increase of 4–7 kg; possible mechanisms were discussed [ ].

An open chart review of 74 hospitalized patients showed a mean weight gain of 6.3 kg and an increase in BMI of 2.1 kg/m2 after they had taken lithium for a mean of 89 days [ ]. Of 47 lithium-treated patients, 14 gained at least 5% of their baseline BMI, 6 gained over 10%, and 2 gained over 15% during an acute treatment phase of unspecified duration, while during the 1-year maintenance phase 11 gained over 5% and 2 gained over 10% [ ].

Combination treatments in bipolar illness cause more weight gain than monotherapy over 3 months. Monotherapy with lithium or other mood stabilizing anticonvulsants in children caused an average weight gain of 1.2 kg; combining two mood stabilizers resulted in a gain of 2.1 kg; combining a mood stabilizer with a second-generation antipsychotic drug resulted in a gain of 5.5 kg [ ].

Comparative studies . In a 1-year, placebo-controlled study of bipolar I prophylaxis (n = 372), weight gain with divalproex, but not with lithium, was significantly more common than with placebo [ ]. A patient who gained 18 kg over 18 months while taking lithium and perphenazine lost 16 kg when the latter was changed to loxapine (she also participated in a weight loss program) [ ]. Whether lithium played a role in the weight gain was unclear.

In a 12-month maintenance study, weight gain was an adverse event in 21% of patients taking divalproex, 13% of those taking lithium, and 7% of those taking placebo [ ]. The divalproex/placebo difference was statistically significant, but the lithium/placebo difference was not.

Mechanism . In 15 consecutive patients, serum leptin concentrations were measured at baseline and after 8 weeks of lithium treatment. There was a significant mean increase of 3.5 ng/ml and serum leptin correlated positively with weight gain (5.9 kg), increased BMI (24–27), and clinical efficacy [ ]. The authors suggested that leptin might play a role in lithium-induced weight gain.

Management . The Expert Consensus Guideline Series, Medication Treatment of Bipolar Disorder 2000, has recommended to “continue present medication, focus on diet and exercise” as the preferred first-line treatment for managing weight gain in patients taking lithium or divalproex. The next approach was to continue medication and add topiramate. Second-line treatments included switching from divalproex to lithium or vice versa, reducing the dosage, and switching to another drug. The addition of an appetite suppressant was a lower second-line recommendation [ ].

Potassium

Episodes of acute hypokalemic paralysis have been associated with long-term lithium therapy [ ].

• A 25-year-old man, who had taken lithium for 5 years, awakened from sleep unable to move his limbs and had a generalized flaccid paralysis with a serum potassium concentration of 2.1 mmol/l. Lithium was withdrawn and he responded to treatment with intravenous potassium chloride.

The diagnosis of acute hypokalemic paralysis was attributed to lithium but without confirmation by rechallenge it was unclear whether this was causal or coincidental.

Sodium

Hypernatremia can occur secondary to dehydration in patients taking lithium and is not uncommon in association with lithium poisoning. Lithium-induced diabetes insipidus is often a contributing factor [ ]. Concurrent antidepressant therapy may attenuate the hypernatremic effect [ ].

Concentrating ability

Lithium often impairs renal concentrating ability, an effect that is related in part to both dosage and duration of treatment [ , ]. While it is initially reversible on withdrawal, it may eventually become irreversible and indicative of structural tubular damage. Impaired concentration is of no clinical consequence in itself, but it may go hand in hand with polyuria (lithium-induced nephrogenic diabetes insipidus), which can sometimes be a social and occupational nuisance and can increase the risk of toxicity secondary to dehydration. These problems can be minimized if the maintenance serum concentration is low, but whether single daily dosing is kinder to the kidney has yet to be resolved. Since the defect is at the level of the kidney (both before and after the site of cyclic AMP generation and probably involving the water channel protein aquaporin-2, a vasopressin-regulated water channel protein [ ], vasopressin (ADH) is unlikely to be effective. A thiazide and/or potassium-sparing diuretic (especially amiloride) can reduce the urine volume, although serum lithium concentrations can rise at the same time. Avoiding hypokalemia is essential, but whether dietary potassium supplementation can also be helpful is not known. Inositol is no longer considered promising.

In a comparison of patients taking long-term lithium (n = 10) or short-term lithium (n = 9) and bipolar patients not taking lithium (n = 10), there was significantly lower creatinine clearance and renal concentrating ability in the long-term group [ ].

Acute and chronic renal insufficiency

Renal insufficiency was attributed to lithium in a 40-year-old who had had nontoxic concentrations for 15 years (interstitial nephropathy on biopsy) [ ] and in a 55-year-old woman who had taken lithium for 6 years (serum creatinine 141 μmol/l [ ]. A few patients develop progressive renal insufficiency that can best be attributed to lithium [ ].

Chronic renal insufficiency (creatinine clearance under 80 ml/minute), for which there was no apparent alternative explanation, developed in 53 patients taking long-term lithium (mean 17.7 years); 7 required periodic dialysis [ ].

After taking lithium for 6 years, a 55-year-old woman development mild rental insufficiency (serum creatinine 1.6 mg/dl) and lithium was withdrawn [ ]

In a follow-up study of 54 patients with lithium-induced renal insufficiency and 20 patients who had been referred for renal biopsy, the authors concluded that lithium-induced chronic renal disease is slowly progressive [ ]. The rate of progression was related to the duration of lithium treatment, and lithium-related end-stage renal disease accounted for a small percentage (0.22%) of all cases of end-stage renal disease in France. The authors strongly suggested that regular monitoring of creatinine clearance is important during long-term lithium management.

Renal size and structure have been evaluated by MRI in 16 patients with renal insufficiency and nephropathy thought to be secondary to lithium [ ]. There were renal microcysts in all patients. All the patients had nephrogenic diabetes insipidus, in which antidiuretic hormone concentrations are raised, and there is evidence that antidiuretic hormone can stimulate the production of renal cysts, by an action mediated via cyclic AMP [ ].

Interstitial nephritis

Lithium-associated changes in kidney morphology include an acute, reversible, and possibly lithium-specific distal tubular lesion and a chronic, nonspecific, and tubulointerstitial nephritis [ ]. The differential diagnosis of the latter is extensive, and it is not clear if lithium is causative.

• A 48-year-old man taking lithium and chlorprothixene had a creatinine clearance of 60 ml/minute and a renal biopsy showing chronic interstitial nephritis [ ].

• Lithium-induced interstitial nephritis (serum creatinine 2.3 mg/dl) occurred in an 89-year-old woman who had taken lithium for 29 years [ ].

Nephrogenic diabetes insipidus

There have been several case reports of lithium-related nephrogenic diabetes insipidus, sometimes associated with dehydration and lithium intoxication [ , ]. This effect is clearly distinct from bipolar illness, as non-psychiatric subjects taking lithium develop a reduced response to desmopressin and a reduced ability to concentrate their urine during water deprivation [ ]. Lithium is a competitive inhibitor of the action of antidiuretic hormone and diabetes insipidus in lithium-treated subjects appears to be mediated by second messengers [ ] with consequent effects on cytoplasmic aquaporin 2 [ , ] or cyclo-oxygenases 1 and 2 (COX-1, COX-2) [ , ].

Nephrogenic diabetes insipidus has been specifically reviewed in the context of a case in which resolution did not occur despite withdrawal of lithium [ ].

Nephrogenic diabetes insipidus secondary to lithium led to severe dehydration in two patients who required intravenous rehydration followed by a thiazide diuretic to reduce urine volume [ ]. One patient had persistent polyuria (6.7 l/day) 57 months after stopping lithium [ ].

• Nephrogenic diabetes insipidus resulted in dehydration and hypernatremia in a 78-year-old man who had taken lithium for 30 years [ ].

• A 78-year-old woman who had taken lithium for 25 years had hypotonic polyuria (4.7 l/day), mild renal insufficiency, and hyperparathyroidism attributed to lithium [ ].

• A 30-year-old woman who became dehydrated secondary to lithium-induced nephrogenic diabetes insipidus developed a superior sagittal sinus thrombosis [ ].

• A 77-year-old woman who had taken lithium for 10 years developed delirium, hypernatremia, prerenal azotemia, and a serum lithium concentration of 1.4 mmol/l; her condition was attributed to dehydration related to partial nephrogenic diabetes insipidus [ ].

• Eight years after stopping lithium because of polydipsia and polyuria, a 55-year-old woman was hospitalized with lethargy, coma, and hypernatremia (sodium concentration 156 mmol/l) after her fluid intake had been restricted [ ].

• Nephrogenic diabetes insipidus in a 63-year-old woman was treated successfully with lithium withdrawal and amiloride [ ].

• A 33-year-old man who had taken multiple medications, including valproic acid and lithium carbonate, started to take olanzapine instead of haloperidol [ ]. Five days later he reported malaise, polyuria, and polydipsia. He had a raised blood glucose, an increased serum osmolality, ketonemia, and glycosuria.

The authors of the last case suggested that the patient had insulin resistance (probably due to olanzapine), which was exacerbated by valproic acid and lithium.

• A 47-year-old woman, who was taking lithium (serum concentration 0.7 mmol/l) for bipolar I disorder, developed an acute abdominal syndrome [ ]. She had a recent history of drinking about 4 l of fluid a day. After surgery, she developed nephrogenic diabetes insipidus, with 19 l/day intake and 15 l/day output. The diuresis fell to 8 l/day over the next 10 days.

The authors wondered whether physiological stress could trigger diabetes insipidus and cited other articles showing that diabetes insipidus due to lithium occurred after surgery or brain injury, during pregnancy, or while fasting. They also suggested that patients who have been stable for a long time might have their lithium withdrawn. Withdrawal of lithium is thought to reverse lithium-induced nephrogenic diabetes insipidus, but the authors reviewed the literature and cited cases of nephrogenic diabetes insipidus that did not reverse after withdrawal of lithium.

• A 76-year-old man developed severe intractable diabetes insipidus which was attributed to lithium [ ]. He was hospitalized for over 2 weeks and eventually died from intestinal hemorrhage. Vigorous efforts were made to treat his polyuria, electrolyte disturbances, hypernatremia, and dehydration. He had been taking chlorpromazine, lithium, and furosemide, along with other medications, and the diagnosis of lithium-induced nephrogenic diabetes insipidus was considered because of a lack of alternative explanations.

The authors reviewed the causes and pathophysiological mechanisms of nephrogenic diabetes insipidus. They also discussed the metabolic effects of lithium, including renal and thyroid effects, hypercalcemia, leukocytosis, and weight gain.

• A 63-year-old man taking long-term lithium for a schizoaffective disorder developed a dural sinus thrombosis and severe hypernatremia and died [ ].

The authors suggested that the sequence of events was lithium-induced nephrogenic diabetes insipidus resulting in hypernatremia followed by the dural sinus thrombosis.

Glomerular dysfunction with lithium is rare, but polyuria and diabetes insipidus are more common [ , ]. This appears to be related to a reduction in cyclic adenosine monophosphate (cAMP) in response to vasopressin [ ]. Generally, diabetes insipidus is more of a nuisance than a significant problem. However, if these patients are fluid deprived they can experience complications. Nearly all cases of lithium-related diabetes insipidus occur while people are taking lithium, and they frequently resolve after withdrawal. However, in one case diabetes insipidus occurred after lithium withdrawal [ ].

Acute hypernatremia occurred in a 55-year-old woman taking lithium, who was made to fast in preparation for surgery for a hip fracture and was loaded with large volumes of fluid during the operation; the authors attributed this to decompensation of undiagnosed nephrogenic diabetes insipidus due to chronic lithium treatment [ ].

Nephrotic syndrome

Nephrotic syndrome (proteinuria, edema, hypoalbuminemia, hyperlipidemia) is a rare and idiosyncratic complication of lithium therapy; it usually resolves on withdrawal, and can recur on rechallenge [ , ]. Lithium-associated nephrotic syndrome occurred in a 59-year-old woman with lithium toxicity (serum concentration 1.9 mmol/l) whose renal biopsy showed focal segmental glomerulosclerosis. Lithium withdrawal led to resolution of edema and marked improvement in proteinuria and albuminemia [ ].

• An 83-year-old man developed nephrotic syndrome while taking lithium [ ].

• An 11-year-old boy who had taken lithium for an unstated duration developed nephrotic syndrome with focal glomerulosclerosis which remitted fully after lithium was withdrawn [ ].

• A 59-year-old woman with lithium-associated nephrotic syndrome (focal segmental glomerulosclerosis on biopsy) had resolution of edema and pleural effusions and marked improvement in albuminemia and proteinuria after withdrawal of lithium [ ].

Renal tubular acidosis

Incomplete distal renal tubular acidosis has been attributed to lithium, but appears to be of no clinical significance [ ].