Masoud Kamali, M.D.
Venkatesh Basappa Krishnamurthy, M.D.
Raman Baweja, M.D.
Erika F.H. Saunders, M.D.
Alan J. Gelenberg, M.D.
After noting the sedating properties of lithium in animals, Cade first described the successful treatment of mania with lithium salts (Cade 1949). The U.S. Food and Drug Administration (FDA) approved lithium for the treatment of acute mania in 1970 and for the maintenance treatment of bipolar disorder 4 years later (Jefferson and Greist 1977). However, lithium did not enter the market easily in the United States. Pharmaceutical companies were reluctant to produce this inexpensive drug that they could not patent (Kline 1973). Lithium is a highly cost-effective treatment for bipolar disorder (Chisholm et al. 2005). A growing number of medications with proven efficacy in bipolar disorder have become available since the introduction of lithium, including anticonvulsants and second-generation (atypical) antipsychotics. In contrast to many of these medications, lithium is available generically and is relatively affordable. These features, added to lithium’s effectiveness, have given it longevity among the psychopharmacological treatment options for bipolar disorder.
Lithium is the lightest alkali metal and a monovalent cation, and it shares some properties with sodium, potassium, and calcium. It is the third element of the periodic table. Substitution of or competition with other cations may contribute to its effects (Baldessarini 1996; Ward et al. 1994).
Lithium is minimally protein bound, does not undergo biotransformation, and is renally eliminated (Kilts 2000). Its narrow therapeutic index necessitates careful drug monitoring. Lithium appears to affect multiple neurotransmitter systems (see “Neurotransmitter Effects” subsection under “Mechanisms of Action”), and it alters second-messenger systems such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Ward et al. 1994).
Lithium is available in multiple preparations, including lithium carbonate tablets and capsules, lithium citrate, and slow-release formulations (Jefferson et al. 1983). Lithium is absorbed from the gastrointestinal tract and is renally excreted unchanged within approximately 24 hours (Baldessarini 1996; Baldessarini and Tarazi 2001). Peak plasma concentrations are reached within 1–2 hours with rapid-release preparations and within 4–5 hours with sustained-release formulations (Finley et al. 1995). Lithium is not protein bound and is evenly distributed in total body water space (Jermain et al. 1991). Lithium excretion is controlled by osmotic factors and is a function of renal sufficiency (Birch et al. 1980). Steady-state concentrations are achieved within 4–5 days (Keck and McElroy 2002).
Despite extensive research, the exact mechanism of lithium’s action as a mood stabilizer has yet to be elucidated. Multiple theories, based on animal models and on limited studies in humans, have been proposed. In the following pages we review theories centering on lithium’s effects on various neurotransmitter systems, on intracellular second-messenger systems, and on signal transduction, as well as a unifying theory focused on lithium’s neuroprotective effects.
Lithium brings about changes in several of the major neurotransmitter systems in the brain, with the overall effect being stimulation of inhibitory transmission and inhibition of excitatory signals (Malhi et al. 2013). Chronic administration of lithium in mice increases and stabilizes glutamate uptake. This modulatory action could, in part, explain lithium’s antimanic effect because it results in overall reduction of an excitatory neurotransmitter (Dixon and Hokin 1998). Lithium also normalizes low cerebrospinal fluid (CSF) levels of γ-aminobutyric acid (an inhibitory neurotransmitter) in bipolar subjects (see Berrettini et al. 1983, 1986; Brambilla et al. 2003).
Lithium enhances norepinephrine and serotonin function in the central nervous system, which could explain its antidepressant effects (Price et al. 1990; Schildkraut et al. 1969; Stern et al. 1969). Of particular interest is lithium’s confirmed antagonistic action at serotonin 1A (5-HT1A) and serotonin 1B (5-HT1B) autoreceptors (Haddjeri et al. 2000; Massot et al. 1999); such action would have the effect of increasing serotonin availability in the synaptic cleft (Shaldubina et al. 2001). Clinically, 5-HT1A receptors may be involved in alleviation of depression, and 5-HT1B receptors may play a role in the regulation of sleep, sensorimotor inhibition, and locomotor activity (Monti et al. 1995; Sipes and Geyer 1996).
There has been much focus on the role of the inositol cycle in the clinical effects of lithium. Lithium is a noncompetitive inhibitor of inositol monophosphatase, depleting free inositol within 5 days of treatment initiation (Berridge et al. 1989). These changes last for 3–4 weeks after lithium is discontinued (Moore et al. 1999). Depletion of free inositol can lead to effects on neurotransmitter and intracellular second-messenger systems linked to the inositol cycle. For example, adrenergic, serotonergic, and cholinergic receptor subtypes are coupled to the cycle via G proteins, and the cycle in turn regulates protein kinase C action, which appears to be influenced by lithium treatment in mania (Hahn et al. 2005).
Of note, depression is associated with low CSF levels of inositol in humans (Barkai et al. 1978). Exogenous inositol can alleviate depression (Levine et al. 1993, 1995) and panic attacks (Benjamin et al. 1995). Belmaker et al. (1996) suggested a complex “pendulum” relationship between inositol and lithium that may provide a basis for understanding lithium’s antimanic and antidepressant effects.
Glycogen synthase kinase 3 (GSK-3) is an enzyme with direct involvement in gene transcription, synaptic plasticity, and cell structure (Malhi et al. 2013). Both lithium (Klein and Melton 1996; Li et al. 2007) and valproate inhibit GSK-3, suggesting that signaling pathways that converge in GSK-3 are important in bipolar disorder (G. Chen et al. 1999). GSK-3 is an inhibitor of the Wnt protein–signaling pathway, which affects neuronal signal transduction. Lithium thus would be predicted to mimic Wnt signaling (Phiel and Klein 2001). Wnt signaling triggers a cascade of events that leads to stimulation of protein kinase C activity (Grahame-Smith 1998; Williams and Harwood 2000). Thus, lithium’s actions on both the inositol cycle and the GSK-3 signaling pathway lead to a common effect on protein kinase C. Because this enzyme’s activity has been reported to be increased in bipolar disorder, protein kinase C inhibitors have been investigated for their potential treatment utility (Zarate and Manji 2009).
A unifying theory posits that lithium’s mechanism of action may be related to its neurotrophic and neuroprotective effects (Quiroz et al. 2010). Patients treated with lithium have larger cortical and hippocampal volumes (Hajek et al. 2012; Moore et al. 2000), and these effects are independent of treatment response (Hajek et al. 2014). One proposed mechanism is lithium’s activation of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), which in turn increases the expression of brain-derived neurotrophic factor and the antiapoptotic bcl-2 (b-cell lymphoma 2) proteins (Alda 2015; Quiroz et al. 2010). Another proposed mechanism is inhibition of GSK-3 and subsequent activation of the Akt neuroprotective pathway (Tajes et al. 2009).
Cade (1949) first published data on the efficacy of lithium in mania more than 60 years ago. As we approach the end of the second decade of the twenty-first century, lithium remains one of the most efficacious treatments for bipolar disorder.
Lithium versus placebo. Lithium has been shown in studies to be more efficacious than placebo in the treatment of acute mania (Bowden et al. 1994, 2005; Fountoulakis et al. 2012; Goodwin et al. 1969; Keck et al. 2009; Kushner et al. 2006; Maggs 1963; Poolsup et al. 2000; Schou et al. 1954; Smith et al. 2007; Stokes et al. 1971; Yildiz et al. 2011). A review of response rates in randomized trials of medication treatment indicated that lithium was at least somewhat efficacious in the treatment of mania, with a response rate of 70% (87 of 124 patients) (Keck et al. 2000).
Lithium versus antipsychotics. Early studies with lithium established its antimanic efficacy relative to first-generation (typical) antipsychotics (Garfinkel et al. 1980; Johnson et al. 1968; Poolsup et al. 2000; Prien et al. 1972; Segal et al. 1998; Shopsin et al. 1975; Spring et al. 1970; Takahashi et al. 1975). A study by Prien et al. (1972) comparing lithium against chlorpromazine found that although chlorpromazine was more effective in reducing manic symptoms in severely ill patients, lithium also reduced symptoms while causing fewer side effects. However, a later meta-analysis concluded that lithium was more effective than chlorpromazine in acute mania (Poolsup et al. 2000). A review of studies by Goodwin and Zis (1979) found lithium to be efficacious in at least 70% of patients, as defined by remission or marked improvement. In a 3-week double-blind study of lithium, haloperidol, and their combination for acute mania, patients who received haloperidol or haloperidol plus lithium had more significant improvement compared with those who received lithium alone (Garfinkel et al. 1980). The combination of lithium and haloperidol was as well tolerated as haloperidol alone. Segal et al. (1998) reported that inpatients with acute mania responded equally well to lithium, haloperidol, and the second-generation agent risperidone.
Lithium has also been studied in comparison with second-generation antipsychotic medications (Berk et al. 1999; Bowden et al. 2005; Fountoulakis et al. 2012; Keck et al. 2009; Kushner et al. 2006; Li et al. 2007; Niufan et al. 2008; Poolsup et al. 2000; Segal et al. 1998; Smith et al. 2007; Yildiz et al. 2011). However, many of these trials were focused on assessing the efficacy of the antipsychotic in a noninferiority approach rather than on demonstrating significant differences between the medications. For example, in a direct comparison with lithium, olanzapine produced greater improvement in manic symptoms over 4 weeks, but it also produced more weight gain (Niufan et al. 2008). By and large, antipsychotics appear to work faster than lithium but carry higher risks for weight gain and other metabolic effects (Fountoulakis et al. 2012; Yildiz et al. 2011).
In a recent study, the addition of lithium to therapy with extended-release quetiapine was found to be more efficacious than add-on placebo (i.e., quetiapine monotherapy) in patients with bipolar mania (Bourin et al. 2014). In a study in which patients with acute mania who had not adequately responded to lithium or divalproex were randomly assigned to receive adjunctive ziprasidone at two dosage ranges (20–40 mg/day or 60–80 mg/day) or placebo for 3 weeks in addition to their mood stabilizer (Sachs et al. 2012b), ziprasidone failed to show clinical or statistical separation from placebo. However, the high proportion of enrolled subjects that did not meet all eligibility criteria for the study may have contributed to the negative findings (Sachs et al. 2012a). In one study, adjunctive gabapentin added to lithium was found to be effective in treating acute mania (Astaneh and Rezaei 2012).
Lithium versus anticonvulsants. Double-blind randomized studies suggest that carbamazepine and lithium are equally effective in the treatment of acute mania (Fountoulakis et al. 2012; Lerer et al. 1987; Okuma et al. 1990; Poolsup et al. 2000; Small et al. 1991; Yildiz et al. 2011). In a direct comparison of lithium and divalproex, Bowden et al. (1994) demonstrated a similar advantage for both agents over placebo, with lithium and divalproex each achieving response in about 48% of patients over 3 weeks. A 12-week study of patients randomly assigned to open treatment with lithium or divalproex yielded additional evidence of the two agents’ comparable efficacy and tolerability over a longer-than-usual study period (Bowden et al. 2008, 2010). A meta-analysis of available randomized controlled trials likewise showed that lithium and valproate were equally effective in acute mania (Poolsup et al. 2000). In a meta-analysis examining the efficacy of lithium, valproate, and carbamazepine in mania, no significant differences in efficacy were found among the three agents (Emilien et al. 1996). However, only some of the included studies were placebo controlled. Anticonvulsants were generally better tolerated than lithium. The presence of neurological abnormalities may predict a better response to anticonvulsants than to lithium in mania. One study found that patients with electroencephalogram abnormalities are more likely to respond to valproate than to lithium (Reeves et al. 2001).
Mixed mania—the co-occurrence of mania with depression—may predict a poorer response to lithium. Freeman et al. (1992), in a direct comparison of lithium and valproate, showed that a favorable response to valproate was associated with high pretreatment depressive symptom scores (Fountoulakis et al. 2012). To further investigate the relation between co-occurring depressive symptoms and treatment response in acute mania, Swann et al. (1997) designed a parallel-group study of lithium versus divalproex and analyzed outcomes relative to the presence of a mixed affective state. They found that the presence of depressive symptoms during an acute manic episode was associated with a poorer response to lithium and a better response to divalproex. Lithium plus topiramate showed no superiority to lithium plus placebo in acute mania (Mirsepassi et al. 2013).
Lithium is equally effective in psychotic and nonpsychotic mania, and early improvement in psychotic symptoms was found to predict higher remission and response rates (de Sousa et al. 2012).
Lithium is considered a first-line treatment for acute bipolar depression (Compton and Nemeroff 2000). Goodwin and Jamison (1990) analyzed placebo-controlled trials in bipolar depression and found that 79% of bipolar patients had either a complete or a partial response to lithium. Placebo-controlled trials showing the efficacy of lithium in bipolar depression include those by Baron et al. (1975), Donnelly et al. (1978), Fieve et al. (1968), Goodwin et al. (1969, 1972), Greenspan et al. (1970), Mendels (1975), and Noyes et al. (1974). These studies generally were small (involving between 3 and 40 patients [Goodwin et al. 1972]).
A recent meta-analytic summary of the above-listed short studies showed a significant advantage for lithium over placebo in bipolar disorder versus unipolar depression (Selle et al. 2014). In a study in which in 802 patients were randomly assigned to 8 weeks of treatment with lithium (600–1,800 mg/day), quetiapine (300 mg/day or 600 mg/day), or placebo (Young et al. 2010), lithium failed to separate significantly from placebo on the main efficacy measure (Montgomery-Åsberg Depression Rating Scale [MADRS] score); however, the study was powered to show an effect for quetiapine, and the mean serum level in lithium-treated subjects was low (0.6 mmol/L).
In the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness) trial, 482 patients with bipolar I or II disorder, the majority (>88%) of whom were experiencing depressive symptoms at study entry (Nierenberg et al. 2016), were randomly assigned to receive lithium plus adjunctive personalized treatment (APT, n=240) or quetiapine plus APT (n=242) for 6 months. In this study, which used new clinical trials methodology, participants in the lithium group were not given a second-generation antipsychotic, and those in the quetiapine group were not given lithium; however, other adjunctive treatments were provided in accordance with best-practice guidelines (Nierenberg et al. 2013). Both groups showed improvement, with 20% achieving sustained response over the study period, and no differences in outcome were detected between the lithium and quetiapine groups (Nierenberg et al. 2013).
In the Lithium Treatment Moderate-dose Use Study (LiTMUS) study (Nierenberg et al. 2013), 283 bipolar I and II patients were randomly assigned to receive optimized personalized treatment (OPT; evidence-based, guideline-informed care) alone or OPT plus lithium at a moderate dosage. The lithium dosage was fixed at 600 mg/day for the first 2 months of the study but was allowed to change based on clinical need after that. Over the 6 months of the trial, the two groups had similar scores on clinical outcome measures, with a sustained remission rate of 27%. Although the addition of lithium conferred no advantage over OPT alone, fewer patients in the lithium-plus-OPT group than in the OPT-only group received second-generation antipsychotics.
In 2004, an expert consensus report recommended lithium as monotherapy for mild to moderate depression in bipolar I disorder and as a component of an initial medication regimen in severe nonpsychotic and psychotic depression (Keck et al. 2004).
In 1974, Dunner and Fieve observed that bipolar patients who had not responded to long-term lithium prophylaxis were more likely to have had four or more mood episodes per year, giving rise to the belief that lithium is not effective in treating rapid cycling. However, subsequent studies have shown that rapid-cycling bipolar disorder responds poorly to most available treatments and that treatment with lithium does improve the burden of illness. In a study examining lithium’s efficacy in rapid-cycling bipolar disorder, Dunner et al. (1977) found that patients who had received lithium for at least 1 year had a higher percentage of “well time” relative to baseline and reported that their mood episodes were shorter and less severe. In an analysis of retrospective and prospective data from 51 patients with rapid-cycling bipolar disorder, Wehr et al. (1988) showed that even among patients with continuous rapid cycling, the manic phases were abbreviated and attenuated. A long-term prospective study of open-label treatment with lithium found a higher rate of recurrence among rapid cyclers versus non–rapid cyclers but similar improvement in symptoms and morbidity (as measured by percentage of time ill, episode frequency, and time to recurrence) (Baldessarini et al. 2000). Finally, a meta-analysis of clinical studies comparing subjects with rapid-cycling and non-rapid-cycling bipolar disorder showed that although lithium was less effective in preventing recurrence among rapid cyclers, it did have beneficial effects on severity and duration of episodes (Kupka et al. 2003). In a 20-month double-blind, parallel-group comparison study, Calabrese et al. (2005) evaluated lithium versus divalproex monotherapy for maintenance treatment in rapid-cycling patients who had been stabilized on a combination of lithium and divalproex. The rates of relapse were similar for lithium-treated and divalproex-treated patients.
Prophylactic or maintenance therapy is often considered after resolution of an acute mood episode. Lithium is the best-studied drug for this indication. Tondo et al. (1998) found lithium to be effective in long-term use (>1 year) in decreasing frequency of mood episodes and “time ill” in patients with bipolar I or bipolar II disorder. Benefits of lithium treatment were not significantly different among patients with psychotic or mixed episodes, rapid cycling, or more classic forms. There was no decrease in efficacy with long-term use. Despite finding evidence for lithium’s efficacy, Kulhara et al. (1999) noted that only 24% of the patients followed in a lithium clinic were free of mood episodes while receiving lithium prophylaxis (average duration of monitoring: 11 years). Treatment nonadherence and/or subtherapeutic lithium serum levels (<0.4 mEq/L), high numbers of psychosocial stressors, higher numbers of depressive episodes before lithium treatment, and poor social support predicted poorer response to lithium prophylaxis. In contrast, starting lithium early in the course of illness predicted a better response to treatment (P<0.001), after episode polarity, sex, age at onset, duration of illness, and duration of lithium prophylaxis were accounted for (Franchini et al. 1999).
In a comparison of lithium, divalproex, and placebo in a 1-year treatment study of patients with bipolar I disorder who had recently recovered from an index manic episode, Bowden et al. (2000) found that median times to 50% survival without any mood episode were 40 weeks for divalproex, 24 weeks for lithium, and 28 weeks for placebo, although the differences were not statistically significant. Patients who received divalproex remained in treatment significantly longer than did those who received lithium.
In a study comparing the prophylactic efficacy of lithium versus placebo, Prien et al. (1973) found that lithium was more effective than placebo in preventing relapses requiring hospitalization. Bowden et al. (2003) compared the efficacy of lamotrigine, lithium, and placebo in preventing relapse to mood episodes among bipolar I subjects with a recent manic or hypomanic episode. After completing a stabilization phase during which treatment with lamotrigine was initiated and other medications were discontinued, subjects were randomly assigned to one of the three drug groups and followed for 18 months. Both lithium and lamotrigine were superior to placebo in prolonging the time to any mood episode, with lithium predominantly effective against manic, hypomanic, or mixed episodes and lamotrigine predominantly effective against depressive episodes. A similar study in bipolar I subjects with a recent depressive episode (Calabrese et al. 2003) reported the same findings. A post hoc analysis of the two studies revealed that lithium not only delayed the time between random assignment and onset of subsyndromal symptoms but also delayed the time between onset of subsyndromal symptoms and emergence of the full mood episode (Frye et al. 2006). In a study by Weisler et al. (2011), bipolar subjects who had been stabilized on quetiapine were randomly assigned to continue quetiapine or be switched to lithium or placebo for up to 104 weeks. Both lithium and quetiapine were superior to placebo in prevention of manic or depressive episodes. In a meta-analysis of 19 randomized controlled blinded trials, Davis et al. (1999) found lithium to be more efficacious than placebo in preventing relapse. In a meta-analysis by Geddes et al. (2004) involving 770 participants, lithium was found to be more effective than placebo in preventing all relapses and manic relapses, but its efficacy in preventing depressive relapses was less robust. In another systematic review and meta-analysis of randomized and quasi-randomized controlled trials, lithium, compared with placebo, was effective in the prevention of relapse in bipolar disorder, especially manic episodes (Beynon et al. 2009). Popovic et al. (2012) used a new metric—the polarity index (number needed to treat [NNT] for prevention of depression divided by NNT for prevention of mania)—to define the profiles of drugs used in the maintenance treatment of bipolar disorder. A polarity index of 1.39 was calculated for lithium, a value indicating its relatively greater antimanic versus antidepressant prophylactic efficacy.
The Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation (BALANCE) study examined the effects of lithium monotherapy, valproate monotherapy, or lithium-plus-valproate combination therapy for relapse prevention in a large international cohort (BALANCE Investigators and Collaborators et al. 2010). More than 300 patients with bipolar I disorder initially completed a “run-in” phase during which they took both lithium and valproate. Of those who tolerated the combination, a subsequent randomization phase assigned subjects to lithium alone, valproate alone, or continued combination treatment for up to 2 years of follow-up. The primary outcome measure was time to new intervention (either medication change or hospitalization) for an emerging mood episode. The study results showed that the combination of lithium and valproate was superior to valproate alone and also suggested that lithium monotherapy was superior to valproate monotherapy. The apparent discrepancy between the latter finding and the conclusions of Bowden et al. (2010) described above may reflect differences in the population studied and in the outcome measures used; alternatively, the valproate dosage in the BALANCE study may have been suboptimal for preventing acute mania.
In a double-blind, randomized maintenance trial of lithium versus olanzapine, bipolar patients experiencing mixed or manic symptoms first received open-label co-treatment with lithium and olanzapine (Tohen et al. 2005). Those whose symptoms remitted were then randomly assigned to monotherapy with either lithium or olanzapine for 52 weeks. Recurrence rates were similar for the two groups, with 38.8% of patients on lithium and 30.0% of those on olanzapine experiencing a relapse. Whereas the two drugs were comparable in prevention of depressive episodes, olanzapine was more effective that lithium in prevention of manic and mixed episodes.
Maintenance dosing. Once-daily dosing of lithium at bedtime yields higher brain-to-serum ratios of lithium levels compared with twice-daily dosing schedules (Soares et al. 2001). Investigators have observed substantial variations in brain lithium levels among people with similar serum lithium levels (González et al. 1993). In a study evaluating maintenance treatment with lithium at dosages yielding low (0.4–0.6 mmol/L) versus standard (0.8–1.0 mmol/L) serum levels, Gelenberg et al. (1989) found that the risk of relapse was 2.6 times higher in patients randomly assigned to maintenance lithium at the low serum level. However, in a reanalysis of the data (Perlis et al. 2002), the higher relapse rate observed with the low serum level was found to be associated with the abrupt reduction in lithium dosage that occurred following randomization in patients who were switched from the standard range to the low range. Thus, an abrupt reduction in lithium dosage may negatively impact the course of illness.
Nolen and Weisler (2013) conducted a post hoc analysis of a double-blind trial in patients with bipolar disorder who were stabilized on quetiapine after a manic, depressive, or mixed episode and then randomly assigned to continue quetiapine or be switched to lithium or placebo for up to 104 weeks. Times to recurrence of any mood episode, as well as to recurrence of a manic or a depressive episode, were longer for patients with serum lithium levels of 0.6–1.2 mEq/L than for patients with serum lithium levels less than 0.6 mEq/L. No difference in time to recurrence was found between patients receiving placebo and patients with lithium levels lower than 0.6 mEq/L, providing evidence that maintenance lithium dosages should be high enough to achieve plasma levels of at least 0.6 mEq/L for prevention of mania and depressive episodes in bipolar disorder. One limitation of this study was that subjects were not randomly assigned to the lithium dosing groups. In a similar post hoc analysis by Severus et al. (2010), subjects were first stabilized on a combination of lithium and olanzapine and then randomly assigned to lithium (at dosages aimed at achieving low [0.6 mmol/L)], medium [0.6–0.79 mmol/L], or high [>0.8 mmol/L] serum levels) or olanzapine (10 mg/day or 10–20 mg/day) for the maintenance phase. The low-serum-level lithium group had a significantly higher risk of relapse to manic or mixed—but not to depressive—episodes compared with the medium- and the high-lithium-level groups and had an increased risk of depression compared with the high-dosage olanzapine group. These findings provide further evidence that lithium levels should be higher than 0.6 mmol/L for optimal protection against relapse to manic, mixed, or depressive episodes.
An analysis of five controlled trials of lithium augmentation of antidepressant treatment in patients with unipolar depression found significant improvement in 56%–96% of patients (Austin et al. 1991; Carvalho et al. 2009; Heit and Nemeroff 1998; Heninger et al. 1983; Kantor et al. 1986; Schöpf et al. 1989; Stein and Bernadt 1993; Zusky et al. 1988). Two separate meta-analyses of randomized, double-blind, placebo-controlled trials in unipolar and bipolar depression evaluated lithium’s efficacy in augmenting and accelerating clinical response to antidepressant treatment (Crossley and Bauer 2007). Although there was firm evidence of lithium’s efficacy as an augmentation agent, there was only modest evidence of its efficacy in accelerating response to antidepressants. In a naturalistic study by Köhler et al. (2013), patients with unipolar depression who had not responded to the first antidepressant they received were 1) started on adjunctive lithium, 2) started on a second-generation antipsychotic (SGA), 3) switched to a different antidepressant, or 4) given a combination of two antidepressants. Patients who received lithium or SGA augmentation showed greater improvement compared with patients switched to another antidepressant or an antidepressant combination. This study was limited by lack of randomization and failure to define nonresponse.
In treatment-refractory depression, open-label data support the addition of lithium to antidepressants, including tricyclic antidepressants (TCAs), trazodone, and selective serotonin reuptake inhibitors (SSRIs) (Bschor et al. 2001; de Montigny et al. 1981, 1983, 1985; Dinan 1993; Fontaine et al. 1991; Price et al. 1986). Double-blind and open-label studies support the use of lithium for augmentation of TCAs, monoamine oxidase inhibitors (MAOIs), trazodone, mirtazapine, and SSRIs (Baumann et al. 1996; Fava et al. 1994; Heninger et al. 1983; Joffe et al. 1993; Kantor et al. 1986; Katona et al. 1995; Nierenberg et al. 2006; Schöpf et al. 1989; Schüle et al. 2009; Zusky et al. 1988). In the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) multisite trial, 15.9% of subjects who did not experience remission with citalopram monotherapy and another medication trial achieved remission after the addition of lithium (Nierenberg et al. 2006). Single studies have found that severe depression (Bschor et al. 2013), weight loss and psychomotor retardation (Alvarez et al. 1997), more than three lifetime major depressive episodes, and a family history of major depressive or bipolar disorder in a first-degree relative (Sugawara et al. 2010) may predict a good response to lithium augmentation in treatment-resistant depression. These studies are limited by small heterogeneous samples, variations in treatment duration, use of mostly nonblinded, retrospective study designs, and absence of a placebo comparator.
Timing of onset of lithium action when the drug is used as an adjunct to antidepressant treatment remains unclear. A meta-analysis of placebo-controlled trials of lithium augmentation in treatment-resistant depression found that a minimum lithium dosage of 800 mg/day (or dosing to produce a serum level of ≥0.5 mEq/L) and a treatment duration of at least 2 weeks favored lithium augmentation as compared with placebo (Bauer et al. 1999).
Up to 50% of bipolar patients attempt suicide (Compton and Nemeroff 2000). In an analysis of studies of lithium treatment (Schou 1998), bipolar patients treated with lithium had a lower overall mortality rate than bipolar patients in general and did not have a significantly higher suicide rate than the general population. Tondo et al. (1997) reviewed studies of the use of lithium in the treatment of major mood disorders; these included 28 studies that involved more than 17,000 patients. Risks of completed and attempted suicides were 8.6-fold higher in patients who were not given lithium compared with those who were. A recent review by Lewitzka et al. (2015) confirmed the antisuicidal effects of lithium. In meta-analyses of studies of lithium treatment in major mood disorders, Tondo et al. (2001), Baldessarini et al. (2006), Guzzetta et al. (2007), and Cipriani et al. (2013) found significantly lower suicide risk for subjects who were receiving treatment with lithium. Methodological problems exist in the studies that have examined lithium and suicide risk, and large-scale prospective studies are needed to inform treatment decisions (Gelenberg 2001). In the first randomized, placebo-controlled trial investigating the effect of adjunctive lithium treatment in prevention of suicidal behavior, which was conducted by Lauterbach et al. (2008), survival analysis showed no significant difference in suicidal acts between lithium- and placebo-treated groups. However, post hoc analysis showed that all completed suicides occurred in the placebo group, suggesting that lithium may be effective in reducing the risk of completed suicide.
In a retrospective cohort population-based study of subjects enrolled in two large integrated health plans with a diagnosis of bipolar disorder who were treated with lithium or divalproex, Goodwin et al. (2003) found that the risks of suicide attempt and suicide death were lower during treatment with lithium than during treatment with divalproex. In a national registry-based follow-up study in Finland exploring the association between medication use and hospitalizations due to a suicide attempt, suicide death, and overall mortality with different psychotropic agents in bipolar disorder, Toffol et al. (2015) found that lithium was associated with a lower risk of suicide attempts as well as decreased suicide and all-cause mortality. In an intriguing systematic review of the association between mortality rates from suicide and the levels of lithium in drinking water, Vita et al. (2015) reported that higher lithium levels in drinking water are associated with reduced suicide risk in the general population.
Lithium is FDA approved for the treatment of bipolar disorder in adolescents and has been shown to be significantly more efficacious than placebo for both bipolar disorder and substance abuse, but not for major depressive disorder (Findling et al. 2015; Geller et al. 1998a, 1998b; Ryan et al. 1999). Lithium had a large effect size in the open-label treatment of acute manic or mixed episodes in children and adolescents (Kowatch et al. 2000) and of acute depressive episodes in adolescents with bipolar I disorder (Patel et al. 2006), and it had a medium effect size in the randomized, placebo-controlled treatment of acute manic or mixed episodes in children and adolescents with bipolar I disorder (Findling et al. 2015). In a randomized, double-blind maintenance trial of lithium versus divalproex in children and adolescents ages 5–17 years (Findling et al. 2005), lithium-treated patients and divalproex-treated patients did not differ in time to relapse. However, in the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children ages 6–15 years, whereas there was no difference in efficacy between lithium and divalproex. The incidence of metabolic side effects was higher with risperidone than with lithium, but the discontinuation rate was higher with lithium than with risperidone (Geller et al. 2012). An earlier study examining predictors of side effects associated with lithium administration in children found that when weight and serum lithium levels were controlled, younger age was associated with more side effects (Campbell et al. 1991).
Lithium has shown effectiveness in elderly patients. In a retrospective trial, significantly more patients age 55 years or older improved with lithium than with valproate, especially in cases of classic mania, whereas the two drugs showed similar response rates when the analysis considered only the cases of mixed mania (S.T. Chen et al. 1999). The lithium serum-level range associated with improvement in elderly patients was similar to the therapeutic range in younger adults: ≥0.8 mmol/L.
Medical comorbidity may be a particular consideration in elderly patients. Volume depletion, use of nonsteroidal anti-inflammatory drugs, or use of thiazide diuretics can increase lithium levels (Stoudemire et al. 1990). The lithium dosage required to achieve therapeutic serum concentrations decreases threefold from middle to old age, with this trend continuing into the ninth and tenth decades of life (Rej et al. 2014b). In a population-based retrospective cohort study involving 1,388 bipolar patients ages 66 years and older, medical hospitalizations, 1-year acute medical health utilization outcomes, and medical comorbidity rates were not different among lithium users as compared with valproate users or nonlithium/nonvalproate users during 1-year follow-up (Rej et al. 2015).
Meta-analyses show that lithium is associated with increased risk of reduced urinary concentrating ability, but there is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low (McKnight et al. 2012). Lithium use is associated with an increased risk of renal failure among the older (ages 50 years and above) age group (Close et al. 2014; Rej et al. 2014a). However, chronic lithium use at lower dosages did not affect renal function in elderly patients with mild cognitive impairment and dementia over a 4-year study period (Aprahamian et al. 2014). Because lithium is cleared almost exclusively by the kidneys, patients with end-stage renal disease receiving hemodialysis cannot eliminate lithium other than through dialysis. Lithium should be given only after a dialysis treatment and need not be given daily (Stoudemire et al. 1990).
Because lithium appears to have neuroprotective effects that may reduce oxidative damage, its potential role in prevention of neurocognitive decline in aging and prevention of Alzheimer’s disease has been suggested (Bachmann et al. 2005; Chen et al. 2000; Cui et al. 2007; Engel et al. 2006; Mohammadianinejad et al. 2014; Phiel et al. 2003; Shao et al. 2005; Su et al. 2004; Tsaltas et al. 2007; Yoshida et al. 2006). A Danish study that followed more than 4,800 patients with newly diagnosed bipolar disorder over 10 years found that long-term treatment with lithium, but not with other psychopharmacological agents, was associated with a reduced risk of developing dementia (Kessing et al. 2010). A study that analyzed data from a national health insurance database in Taiwan concluded that lithium use was significantly related to a reduced risk of stroke in patients with bipolar disorder. The association between lithium use and reduced stroke risk was strongest for patients who received the highest lithium dosages, experienced the longest durations of lithium treatment, and had the highest rates of lithium exposure (Lan et al. 2015).
The risks and benefits of lithium treatment must be carefully assessed in the context of pregnancy and breast feeding. Undertreated or untreated women with bipolar disorder are at increased risk for perinatal complications and poor pregnancy outcomes (Jablensky et al. 2005; Lee and Lin 2010). A prospective observational study by Diav-Citrin et al. (2014) that compared lithium-exposed pregnancies with disease-matched and nonteratogenic-exposed control pregnancies found higher rates of miscarriage and preterm delivery in the lithium-exposed group compared with the nonteratogenic exposure group, but no difference in rates of stillbirth or ectopic pregnancy. Data suggest that lithium exposure during pregnancy is less harmful than experts believed in past decades (Cohen et al. 1994). In fact, although the overall risk of Ebstein’s anomaly—a rare cardiac malformation with an incidence of 1 in 20,000 live births—may be higher with lithium use (relative risk of 10–20 vs. the general population) than without, the prevalence associated with first-trimester lithium exposure is 0.05%–0.1% (Cohen and Rosenbaum 1998). In the observational study by Diav-Citrin et al. (2014), rates of major congenital anomalies after exclusion of genetic or cytogenetic anomalies were not significantly different in the lithium-exposed group compared with the bipolar patients not exposed to lithium and the nonteratogenic exposure group (Diav-Citrin et al. 2014). Cardiovascular anomalies occurred more frequently in the lithium-exposed group compared with the nonteratogenic exposure group, but after exclusion of anomalies that spontaneously resolved, there were no differences between the groups, and there was also no difference between groups in the rates of noncardiovascular anomalies (Diav-Citrin et al. 2014). The risk of cardiovascular anomalies with lithium is substantially lower than the risk of neural tube defects associated with some anticonvulsants used for mood stabilization. Overall, lithium is not a high-risk teratogen.
Lithium freely crosses the placenta. Lithium-exposed neonates are more likely than nonexposed neonates to be born preterm, to have lower birthweights, and to have longer hospital stays (Newport et al. 2005). Because birth complications are directly correlated with placental lithium concentrations, brief suspension (24–48 hours) of lithium therapy before delivery has been suggested (Newport et al. 2005).
Although lithium is today considered a first-line treatment for bipolar disorder during pregnancy (Larsen et al. 2015), many women wish to discontinue all psychotropic medications or to discontinue lithium (McCrea et al. 2015) during pregnancy. In a longitudinal study of 89 women with bipolar disorder who continued or discontinued mood stabilizer treatment during pregnancy, Viguera et al. (2007b) reported an overall risk of recurrence of 71%. Risk of recurrence was twofold greater in women who discontinued mood stabilizer treatment compared with those who did not, and time to recurrence was 11 times shorter if the mood stabilizer was discontinued abruptly instead of gradually. Risk of recurrence was 1.6 times higher in women using a mood stabilizer other than lithium (Viguera et al. 2007b). In an earlier study of relapse after lithium discontinuation in pregnant and nonpregnant women with bipolar disorder, Viguera et al. (2000) found that rates of relapse were initially similar in the two groups but increased sharply during the postpartum period (70% vs. 24% in nonpregnant patients matched for time after discontinuation) (Viguera et al. 2000). This high risk of recurrence has prompted experts in the field to recommend postpartum prophylactic treatment with a mood stabilizer for women with bipolar disorder (Cohen et al. 1995).
Lithium is secreted in breast milk and is passed on to the infant. For this reason, and also because of a small number of case reports of adverse effects in nursing infants of mothers taking lithium, the American Academy of Pediatrics (AAP) had previously considered lithium use to be contraindicated in breast-feeding women (Chaudron and Jefferson 2000). However, that recommendation was revised in 2001 to the recommendation that lithium be used with caution in breast feeding due to reports of adverse events (American Academy of Pediatrics Committee on Drugs 2001). The Committee on Drugs of the AAP now reports that lithium is present at clinically significant levels (10% or more of therapeutic maternal plasma concentration) in human milk. The AAP currently recommends that in addition to receiving counseling about the benefits of breast feeding, parents be informed of the potential risks for infants exposed to clinically significant levels and cautioned that the long-term effects of this exposure are unknown (Sachs and Committee on Drugs 2013). In a study of 10 mother–infant pairs, serum lithium levels in the infants ranged from 0.09 to 0.3 mEq/L (mean 0.16 mEq/L). Transient elevations in infant thyroid-stimulating hormone, blood urea nitrogen, and creatinine levels were observed without evident long-term effects (Viguera et al. 2007a). The study authors concluded that breast feeding in the context of lithium therapy may be considered reasonable for a healthy infant when the mother’s bipolar disorder is clinically stable, lithium monotherapy or a simple medication regimen is being used, and the pediatrician is supportive of the mother’s breast feeding while she is being treated with lithium.
Before lithium therapy is started, a medical history should be obtained, as well as baseline renal laboratory tests (blood urea nitrogen, creatinine level), thyroid function tests, and an electrocardiogram for patients older than 40 years (American Psychiatric Association 2002, McKnight et al. 2012). The American Psychiatric Association practice guideline for the treatment of bipolar disorder suggests that renal function should be assessed every 2–3 months and thyroid function should be tested once or twice during the first 6 months of treatment. After the first 6 months, renal laboratory tests and thyroid function tests should be monitored every 6–12 months or as clinically indicated (American Psychiatric Association 2002; McKnight et al. 2012; Shine et al. 2015).
Cognitive side effects and weight gain have been reported to be the most disturbing side effects experienced in patients receiving lithium maintenance treatment, whereas self-reported noncompliance was mostly associated with lithium’s effects on cognition and coordination (Gitlin et al. 1989). Stoll et al. (1996) reported on a case series in which seven patients with lithium-associated cognitive deficits improved when switched to treatment with divalproex sodium. Lithium is associated with clinically significant weight gain (>7%) (McKnight et al. 2012), which may pose a greater risk for patients who are obese before commencement of lithium treatment compared with those who are at normal weight (Bowden et al. 2006).
Neurotoxicity, delirium, and encephalopathy have been reported with lithium use. Specific populations with underlying neurological vulnerability have been noted to be at higher risk. Also, certain circumstances, such as concomitant electroconvulsive therapy or use of other psychotropics—especially first-generation antipsychotics—have been found to increase the risk of neurotoxic adverse effects from lithium treatment.
Neurotoxic reactions are potentially irreversible. Permanent neurological deficits reported after episodes of lithium intoxication (Apte and Langston 1983; Donaldson and Cuningham 1983) have included deficits in recent memory, ataxia, and movement disorders. Early hemodialysis may help prevent permanent sequelae in these cases. Donaldson and Cuningham (1983) also reported persistent neurological sequelae of lithium toxicity involving multiple sites within the nervous system. In a case series of 90 patients, Adityanjee et al. (2005) reported that the most common sequela was cerebellar dysfunction. The typical neurological signs of irreversible lithium neurotoxicity include cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction, and dementia (Ivkovic and Stern 2014). Himmelhoch et al. (1980) found a greater incidence of lithium-induced neurotoxicity in the elderly. Other risk factors include longer duration of exposure to higher lithium levels and presence of medical comorbidities, including nephrogenic diabetes insipidus, abnormal thyroid function and impaired renal function, preexisting neurological disease, and drug combinations including antipsychotics (Ivkovic and Stern 2014; Netto and Phutane 2012; Oakley et al. 2001).
A fine postural tremor affects between 4% and 65% of patients who receive lithium (Gelenberg and Jefferson 1995). A severe tremor may indicate toxicity. Elimination of caffeine may actually worsen tremor because renal lithium clearance can be reduced with reduction of caffeine intake (Jefferson 1988). Lithium tremor, which resembles essential tremor, may worsen with age.
In a chart review of 135 patients who received maintenance treatment with lithium, 38% had abnormal values on thyroid function tests (thyroid-stimulating hormone and/or free thyroxine index), with an association between laboratory abnormalities and length of time on lithium (Fagiolini et al. 2006). In a systematic review and meta-analysis, McKnight et al. (2012) reported that in comparison with placebo-treated subjects, lithium-treated patients had a sixfold higher risk of hypothyroidism and increased levels of thyroid-stimulating hormone. In a retrospective study of 209 patients who received lithium, Kirov (1998) found that 14.9% of the females and 3.4% of the males developed hypothyroidism. Female patients and patients older than 50 years were more likely to develop hypothyroidism (Kirov 1998; Shine et al. 2015). Other reports have suggested that subclinical hypothyroidism during lithium therapy is much more common than previous cross-sectional studies had indicated (Lombardi et al. 1993). A family history of thyroid disease may lead to earlier onset of the hypothyroidism that occurs with lithium use (Kusalic and Engelsmann 1999). Female patients with high serum lithium concentrations should have regular thyroid function testing (Shine et al. 2015).
Lithium has been associated with hypercalcemia and hyperparathyroidism (Saunders et al. 2009). A meta-analysis by McKnight et al. (2012) found that lithium-treated patients showed a 10% increase in levels of parathyroid hormone and calcium (McKnight et al. 2012) compared with control subjects. Similar increases in parathyroid hormone (Albert et al. 2013) and calcium (Albert et al. 2013; Shine et al. 2015) in lithium-treated patients have been reported in other studies as well. Monitoring of calcium levels at baseline and yearly, or more frequently in the presence of clinical symptoms, is suggested (McKnight et al. 2012).
Lithium has multiple renal effects, including those that occur early in treatment and those that occur with chronic use. Lithium can induce tubular dysfunction early in treatment, with reduced urinary concentrating capacity developing over the first 8 weeks of treatment. Nephrogenic diabetes insipidus occurs in 20%–87% of patients on lithium (Azab et al. 2015; Markowitz et al. 2000; Stone 1999). These effects may be partially mediated by lithium’s action on water and sodium channels in the kidney (Grünfeld and Rossier 2009); thus, there has been renewed interest in using amiloride, a sodium channel–blocking diuretic, in an attempt to modify lithium’s toxicity (Azab et al. 2015; Bedford et al. 2008).
Another important renal effect of lithium is chronic kidney disease, which tends to occur after 10–20 years of lithium treatment (Presne et al. 2003) at an estimated prevalence of 1.2% (Bendz et al. 2010) to 21% (Lepkifker et al. 2004), depending on the definition of renal insufficiency used. However, the risk of progressing to end-stage renal disease is small (0.5%–1%) (Bendz et al. 2010; Tredget et al. 2010). The clearest risk factors are duration of lithium use (Bendz et al. 2010; Bocchetta et al. 2015; Castro et al. 2016; Presne et al. 2003), dosing of lithium more than once a day (Castro et al. 2016), and higher serum lithium levels (Castro et al. 2016; Shine et al. 2015); however, additional possible risk factors are older age (Bendz et al. 2010; Bocchetta et al. 2015; Castro et al. 2016; Close et al. 2014; Presne et al. 2003), female sex (Castro et al. 2016; Shine et al. 2015), previous episodes of lithium toxicity, and presence of comorbid disorders (Castro et al. 2016; Lepkifker et al. 2004). The potential for chronic renal disease is the reason that close laboratory monitoring is required for patients on long-term lithium treatment (Shine et al. 2015). Once-daily dosing and maintaining low lithium levels when possible may be helpful in preventing long-term renal damage (Castro et al. 2016; Malhi and Tanious 2011). The decision of whether to stop lithium in the setting of renal impairment must be made collaboratively by the patient, the psychiatrist, and the nephrologist. Chronic kidney disease can progress to renal failure even after lithium is stopped; however, with mild or moderate renal dysfunction, there may be improvement if a change is made (Grünfeld and Rossier 2009).
Lithium intoxication has been reported to cause cardiac alterations, including sinus bradycardia and sinus node dysfunction (Steckler 1994). Sinus node dysfunction was found to be more prevalent among patients who had been taking lithium for at least a year than among age-matched control subjects, although clinically significant dysfunction was uncommon (Rosenqvist et al. 1993). Also, cases of atrioventricular block in patients with therapeutic lithium levels have been reported (Martin and Piascik 1985). Electrocardiographic T-wave changes, as well as ventricular irritability, may occur (Mitchell and Mackenzie 1982). In patients with clinical indications for lithium use, the presence of cardiovascular disease does not constitute a contraindication to lithium use. Dosage adjustment and frequent cardiac monitoring are essential for the safe use of lithium in patients with cardiac disease (Tilkian et al. 1976). Because of the risk of sinus node dysfunction and other cardiac effects, careful monitoring of the pulse and electrocardiographic monitoring are recommended in patients older than 50 years (Roose et al. 1979).
Lithium is commonly used in combination with other mood stabilizers, and although such combinations can be synergistic, polypharmacy may increase the risk of adverse reactions (Freeman and Stoll 1998; Lenox et al. 1996). The combination of lithium and valproate is often used in refractory mania. Interactions may include additive side effects, such as sedation, tremor, or weight gain, but the pharmacokinetics of lithium are not altered by the addition of valproate (Granneman et al. 1996). Lithium and carbamazepine have been combined for bipolar disorder refractory to lithium alone, but this combination may increase the risk of neurotoxicity (Chaudhry and Waters 1983; Frances et al. 1996; Kishimoto 1992; Shukla et al. 1984, 1985; Small et al. 1995). Topiramate exhibits no pharmacokinetic interactions with lithium (Bialer et al. 2004). There are inconsistent reports about interactions between lithium and lamotrigine; whereas Chen et al. (1999) found no significant alterations in the pharmacokinetics of lithium in 20 healthy volunteers, another study showed that co-treatment with lithium may lower the serum concentration of lamotrigine (Reimers et al. 2005). Gabapentin is also used adjunctively in the treatment of bipolar disorder, and because gabapentin has no known drug interactions, it is likely safe with lithium use (Frye et al. 1998; Vollmer et al. 1986). Benzodiazepines also do not interact with lithium (Adler 1986; Modell et al. 1985; Sachs et al. 1990a, 1990b).
Although many investigators have reported safe and efficacious results from combining lithium and first-generation antipsychotics (Baastrup et al. 1976; Bigelow et al. 1981; Carman et al. 1981; Garfinkel et al. 1980; Goldney and Spence 1986), neurotoxicity and even tardive dyskinesia can occur (Cohen and Cohen 1974; Dinan and Kohen 1989; Mani et al. 1996; Mann et al. 1983; Miller et al. 1986; Perényi et al. 1983, 1984; Spring 1979; Spring and Frankel 1981). Goodwin and Jamison (1990) recommended that when incorporating a first-generation antipsychotic into a regimen of lithium therapy, the antipsychotic should be used at lower dosages, and lithium levels should be maintained below 1.0 mEq/L.
The use of lithium with second-generation antipsychotics also may result in adverse reactions. Use of clozapine with lithium may cause diabetic ketoacidosis, neuroleptic malignant syndrome, and neurological side effects (Blake et al. 1992; Garcia et al. 1994; Lemus et al. 1989; Peterson and Byrd 1996; Pope et al. 1986). Some investigators have reported safe and effective use of risperidone and lithium (Ghaemi et al. 1997; Tohen et al. 1996), although adverse effects, including fever, increased white blood cell counts, increased creatine phosphokinase levels, and delirium, also have been reported (Chen and Cardasis 1996; Swanson et al. 1995). Preliminary data suggest that the combination of lithium and olanzapine is efficacious and well tolerated in acute mania (Madhusoodanan et al. 2000; Sanger et al. 2001). Quetiapine coadministered with lithium did not result in clinically important pharmacokinetic interactions (Potkin et al. 2002). Augmentation of lithium with aripiprazole produced rapid and significant improvement in manic symptoms that was sustained over the long term (Vieta et al. 2008), and there were no clinically meaningful effects on the pharmacokinetics of either drug (Boulton et al. 2012). There were no significant interactions between lurasidone and lithium, and no dosage adjustment for lurasidone was needed when administered with lithium (Chiu et al. 2014).
Lithium is often used concomitantly with antidepressants in the treatment of bipolar depression and refractory unipolar depression. Serotonin syndrome—a constellation of mental status and behavioral changes (either agitation or sedation), motor symptoms (restlessness, weakness, hyperreflexia, or ataxia), and autonomic dysfunction (nausea and/or vomiting, dizziness, sweating, fever) (Lejoyeux et al. 1994)—has been reported with the use of lithium and serotonergic antidepressants (Adan-Manes et al. 2006; Fagiolini et al. 2001; Karle and Bjørndal 1995; Mekler and Woggon 1997; Muly et al. 1993; Ohman and Spigset 1993; Shahani 2012; Sobanski et al. 1997).
When lithium is used concurrently with nonsteroidal anti-inflammatory drugs, signs and symptoms of toxicity and lithium levels must be monitored more carefully because nonsteroidal anti-inflammatory drugs increase the risk of toxicity (Grandjean and Aubry 2009; Johnson et al. 1993).
Because lithium excretion relies on renal clearance, diuretic medications may affect lithium levels, depending on their site of action. Thiazide diuretics trigger a compensatory increase in reabsorption in the proximal tubule and lead to elevations in lithium levels, whereas loop diuretics do not promote lithium reabsorption and do not greatly affect lithium levels (Finley et al. 1995). Osmotic diuretics enhance lithium excretion and may serve to counteract lithium toxicity, and either no change or a slight increase in lithium levels has been reported with potassium-sparing diuretics.
Neurotoxic and other adverse reactions have been associated with the concomitant administration of lithium with calcium channel blockers (Dubovsky et al. 1987; Finley et al. 1995; Helmuth et al. 1989; Wright and Jarrett 1991). Angiotensin-converting enzyme inhibitors or angiotensin receptor 1 blockers may raise lithium levels (DasGupta et al. 1992; Finley et al. 1996; Lazarczyk and Giannakopoulos 2014). Serum lithium levels may increase in the context of sodium restriction (Bennett 1997). Theophylline and caffeine can decrease lithium concentrations (Cook et al. 1985). Lactulose may result in lithium toxicity, possibly by volume depletion, as reported in a case series (Bregman et al. 2014).
Lithium is an important option in the evidence-based rational treatment of bipolar disorder. Bipolar disorder affects between 1% and 5% of the population (Akiskal et al. 2000) and causes significant morbidity and mortality, and the diagnosis of bipolar disorder carries a high risk for suicide. A summary published in 1990 estimated that 25%–50% attempt suicide and 19% complete suicide (Goodwin and Jamison 1990); however, a recent analysis estimated that the pooled suicide rate for bipolar disorder was 164 per 100,000 person-years, with individuals with bipolar disorder accounting for 3.4%–14% of all suicide deaths (Schaffer et al. 2015).
Lithium has been shown to be effective for acute mania and bipolar depression and as a prophylactic treatment for bipolar disorder. Some data suggest that conditions such as comorbid neurological illness and mixed episodes may be indicators of illness that is more responsive to mood stabilizers other than lithium. Evidence also suggests that lithium can play a role in the treatment of refractory unipolar depression in patients at risk for suicide. Lithium may be less risky than anticonvulsants in pregnancy. Although we continually seek new treatments and hope that they will be more efficacious and better tolerated than older medications, for now lithium remains an important treatment option.
Adan-Manes J, Novalbos J, López-Rodríguez R, et al: Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 31(4):397–400, 2006 16882112
Adityanjee MKR, Munshi KR, Thampy A: The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 28(1):38–49, 2005 15714160
Adler LW: Mixed bipolar disorder responsive to lithium and clonazepam. J Clin Psychiatry 47(1):49–50, 1986 3079750
Akiskal HS, Bourgeois ML, Angst J, et al: Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 59 (suppl 1):S5–S30, 2000 11121824
Albert U, De Cori D, Aguglia A, et al: Lithium-associated hyperparathyroidism and hypercalcaemia: a case-control cross-sectional study. J Affect Disord 151(2):786–790, 2013 23870428
Alda M: Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry 20(6):661–670, 2015 25687772
Alvarez E, Pérez-Solá V, Pérez-Blanco J, et al: Predicting outcome of lithium added to antidepressants in resistant depression. J Affect Disord 42(2–3):179–186, 1997 9105959
American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk. Pediatrics 108(3):776–789, 2001 11533352
American Psychiatric Association: Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 159 (4 suppl):1–50, 2002 11958165
Aprahamian I, Santos FS, dos Santos B, et al: Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry 75(7):e672–e678, 2014 25093483
Apte SN, Langston JW: Permanent neurological deficits due to lithium toxicity. Ann Neurol 13(4):453–455, 1983 6838176
Astaneh AN, Rezaei O: Adjunctive treatment with gabapentin in bipolar patients during acute mania. Int J Psychiatry Med 43(3):261–271, 2012 22978083
Austin MPV, Souza FGM, Goodwin GM: Lithium augmentation in antidepressant-resistant patients. A quantitative analysis. Br J Psychiatry 159:510–514, 1991 1836411
Azab AN, Shnaider A, Osher Y, et al: Lithium nephrotoxicity. Int J Bipolar Disord 3(1):28, 2015 26043842
Baastrup PC, Hollnagel P, Sorensen R, Schou M: Adverse reactions in treatment with lithium carbonate and haloperidol. JAMA 236(23):2645–2646, 1976 1036539
Bachmann RF, Schloesser RJ, Gould TD, Manji HK: Mood stabilizers target cellular plasticity and resilience cascades: implications for the development of novel therapeutics. Mol Neurobiol 32(2):173–202, 2005 16215281
BALANCE Investigators and Collaborators, Geddes JR, Goodwin GM, Rendell J, et al: Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 375(9712):385–395, 2010 20092882
Baldessarini RJ: Drugs and the treatment of psychiatric disorders: depression and mania, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th Edition. Edited by Hardman JG, Limbird LE. New York, McGraw-Hill, 1996, pp 431–459
Baldessarini RJ, Tarazi FI: Drugs and the treatment of psychiatric disorders: psychosis and mania, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition. Edited by Hardman JG, Limbird LE. New York, McGraw-Hill, 2001, pp 485–520
Baldessarini RJ, Tondo L, Floris G, Hennen J: Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. J Affect Disord 61(1–2):13–22, 2000 11099736
Baldessarini RJ, Tondo L, Davis P, et al: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 8(5 Pt 2):625–639, 2006 17042835
Barkai AI, Dunner DL, Gross HA, et al: Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry 13(1):65–72, 1978 623854
Baron M, Gershon ES, Rudy V, et al: Lithium carbonate response in depression. Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history. Arch Gen Psychiatry 32(9):1107–1111, 1975 1101845
Bauer M, Dopfmer S, Rudy V, et al: Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol 19(5):427–434, 1999 10505584
Baumann P, Nil R, Souche A, et al: A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 16(4):307–314, 1996 8835706
Bedford JJ, Weggery S, Ellis G, et al: Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol 3(5):1324–1331, 2008 18596116
Belmaker RH, Bersudsky Y, Agam G, et al: How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory. Annu Rev Med 47:47–56, 1996 8712796
Bendz H, Schön S, Attman PO, Aurell M: Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int 77(3):219–224, 2010 19940841
Benjamin J, Levine J, Fux M, et al: Inositol treatment for panic disorder: a double-blind placebo-controlled crossover trial. Am J Psychiatry 152:1084–1086, 1995 7793450
Bennett WM: Drug interactions and consequences of sodium restriction. Am J Clin Nutr 65 (2 suppl):678S–681S, 1997 9022564
Berk M, Ichim L, Brook S: Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int Clin Psychopharmacol 14(6):339–343, 1999 10565800
Berrettini WH, Nurnberger JI Jr, Hare TA, et al: Reduced plasma and CSF γ-aminobutyric acid in affective illness: effect of lithium carbonate. Biol Psychiatry 18(2):185–194, 1983 6403063
Berrettini WH, Nurnberger JI Jr, Hare TA, et al: CSF GABA in euthymic manic-depressive patients and controls. Biol Psychiatry 21(8–9):844–846, 1986 3730464
Berridge MJ, Downes CP, Hanley MR: Neural and developmental actions of lithium: a unifying hypothesis. Cell 59(3):411–419, 1989 2553271
Beynon S, Soares-Weiser K, Woolacott N, et al: Pharmacological interventions for the prevention of relapse in bipolar disorder: a systematic review of controlled trials. J Psychopharmacol 23(5):574–591, 2009 18635701
Bialer M, Doose DR, Murthy B, et al: Pharmacokinetic interactions of topiramate. Clin Pharmacokinet 43(12):763–780, 2004 15355124
Bigelow LB, Weinberger DR, Wyatt RJ: Synergism of combined lithium-neuroleptic therapy: a double-blind, placebo-controlled case study. Am J Psychiatry 138(1): 81–83, 1981 7192495
Birch NJ, Greenfield AA, Hullin RP: Pharmacodynamic aspects of long-term prophylactic lithium. Int Pharmacopsychiatry 15(2):91–98, 1980 7440099
Blake LM, Marks RC, Luchins DJ: Reversible neurologic symptoms with clozapine and lithium. J Clin Psychopharmacol 12(4):297–299, 1992 1527237
Bocchetta A, Ardau R, Fanni T, et al: Renal function during long-term lithium treatment: a cross-sectional and longitudinal study. BMC Med 13(1):12, 2015 25604586
Boulton DW, Kollia GD, Mallikaarjun S, Kornhauser DM: Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole. J Clin Pharm Ther 37(5):565–570, 2012 22943745
Bourin MS, Severus E, Schronen JP, et al: Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study. Int J Bipolar Disord 2:14, 2014 25505693
Bowden CL, Brugger AM, Swann AC, et al; The Depakote Mania Study Group: Efficacy of divalproex vs lithium and placebo in the treatment of mania (erratum in JAMA 271:1830, 1994). JAMA 271(12): 918–924, 1994 8120960
Bowden CL, Calabrese JR, McElroy SL, et al; Divalproex Maintenance Study Group: A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 57(5):481–489, 2000 10807488
Bowden CL, Calabrese JR, Sachs G, et al; Lamictal 606 Study Group: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 60(4):392–400, 2003 12695317
Bowden CL, Grunze H, Mullen J, et al: A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 66(1):111–121, 2005 15669897
Bowden CL, Calabrese JR, Ketter TA, et al: Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J Psychiatry 163(7):1199–1201, 2006 16816224
Bowden C, Göğüş A, Grunze H, et al: A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int Clin Psychopharmacol 23(5):254–262, 2008 18703934
Bowden CL, Mosolov S, Hranov L, et al: Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int Clin Psychopharmacol 25(2):60–67, 2010 20101186
Brambilla P, Perez J, Barale F, et al: GABAergic dysfunction in mood disorders. Mol Psychiatry 8(8):721–737, 715, 2003 12888801
Bregman A, Fritz K, Xiong GL: Lactulose-associated lithium toxicity: a case series. J Clin Psychopharmacol 34(6):742–743, 2014 25133791
Bschor T, Canata B, Müller-Oerlinghausen B, et al: Predictors of response to lithium augmentation in tricyclic antidepressant-resistant depression. J Affect Disord 64(2):261–265, 2001 11313093
Bschor T, Uhr M, Baethge C, et al: Acute antidepressive efficacy of lithium monotherapy, not citalopram, depends on recurrent course of depression. J Clin Psychopharmacol 33(1):38–44, 2013 23277245
Cade JF: Lithium salts in the treatment of psychotic excitement. Med J Aust 2(10):349–352, 1949 18142718
Calabrese JR, Bowden CL, Sachs G, et al; Lamictal 605 Study Group: A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 64(9):1013–1024, 2003 14628976
Calabrese JR, Shelton MD, Rapport DJ, et al: A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry 162(11):2152–2161, 2005 16263857
Campbell M, Silva RR, Kafantaris V, et al: Predictors of side effects associated with lithium administration in children. Psychopharmacol Bull 27(3):373–380, 1991 1775612
Carman JS, Bigelow LB, Wyatt RJ: Lithium combined with neuroleptics in chronic schizophrenic and schizoaffective patients. J Clin Psychiatry 42(3):124–128, 1981 6110654
Carvalho AF, Machado JR, Cavalcante JL: Augmentation strategies for treatment-resistant depression. Curr Opin Psychiatry 22(1):7–12, 2009 19122528
Castro VM, Roberson AM, McCoy TH, et al: Stratifying risk for renal insufficiency among lithium-treated patients: an electronic health record study. Neuropsychopharmacology 41(4):1138–1143, 2016 26294109
Chaudhry RP, Waters BG: Lithium and carbamazepine interaction: possible neurotoxicity. J Clin Psychiatry 44(1):30–31, 1983 6401711
Chaudron LH, Jefferson JW: Mood stabilizers during breastfeeding: a review. J Clin Psychiatry 61(2):79–90, 2000 10732654
Chen B, Cardasis W: Delirium induced by lithium and risperidone combination. Am J Psychiatry 153(9):1233–1234, 1996 8780436
Chen C, Veronese L, Yin Y: The effects of lamotrigine on the pharmacokinetics of lithium. Br J Clin Pharmacol 50(3):193–195, 2000 10971302
Chen G, Huang LD, Jiang YM, Manji HK: The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72(3):1327–1330, 1999 10037507
Chen G, Rajkowska G, Du F, et al: Enhancement of hippocampal neurogenesis by lithium. J Neurochem 75(4):1729–1734, 2000 10987856
Chen ST, Altshuler LL, Melnyk KA, et al: Efficacy of lithium vs. valproate in the treatment of mania in the elderly: a retrospective study. J Clin Psychiatry 60(3):181–186, 1999 10192594
Chisholm D, van Ommeren M, Ayuso-Mateos JL, Saxena S: Cost-effectiveness of clinical interventions for reducing the global burden of bipolar disorder. Br J Psychiatry 187:559–567, 2005 16319409
Chiu YY, Ereshefsky L, Preskorn SH, et al: Lurasidone drug-drug interaction studies: a comprehensive review. Drug Metabol Drug Interact 29(3):191–202, 2014 24825095
Cipriani A, Hawton K, Stockton S, Geddes JR: Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 346:f3646, 2013 23814104
Close H, Reilly J, Mason JM, et al: Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One 9(3):e90169, 2014 24670976
Cohen LS, Rosenbaum JF: Psychotropic drug use during pregnancy: weighing the risks. J Clin Psychiatry 59 (suppl 2):18–28, 1998 9559756
Cohen LS, Friedman JM, Jefferson JW, et al: A reevaluation of risk of in utero exposure to lithium. JAMA 271(2):146–150, 1994 8031346
Cohen LS, Sichel DA, Robertson LM, et al: Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry 152(11): 1641–1645, 1995 7485628
Cohen WJ, Cohen NH: Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 230(9):1283–1287, 1974 4479505
Compton MT, Nemeroff CB: The treatment of bipolar depression. J Clin Psychiatry 61 (suppl 9):57–67, 2000 10826663
Cook BL, Smith RE, Perry PJ, Calloway RA: Theophylline-lithium interaction. J Clin Psychiatry 46(7):278–279, 1985 4008452
Crossley NA, Bauer M: Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 68(6):935–940, 2007 17592920
Cui J, Shao L, Young LT, Wang JF: Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience 144(4):1447–1453, 2007 17184924
DasGupta K, Jefferson JW, Kobak KA, Greist JH: The effect of enalapril on serum lithium levels in healthy men. J Clin Psychiatry 53(11):398–400, 1992 1459971
Davis JM, Janicak PG, Hogan DM: Mood stabilizers in the prevention of recurrent affective disorders: a meta-analysis. Acta Psychiatr Scand 100(6):406–417, 1999 10626918
de Montigny C, Grunberg F, Mayer A, Deschenes JP: Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry 138:252–256, 1981 7272619
de Montigny C, Cournoyer G, Morissette R, et al: Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry 40(12):1327–1334, 1983 6418109
de Montigny C, Elie R, Caillé G: Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study. Am J Psychiatry 142(2):220–223, 1985 3918468
de Sousa RT, Busnello JV, Forlenza OV, et al: Early improvement of psychotic symptoms with lithium monotherapy as a predictor of later response in mania. J Psychiatr Res 46(12):1564–1568, 2012 23000368
Diav-Citrin O, Shechtman S, Tahover E, et al: Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. Am J Psychiatry 171(7):785–794, 2014 24781368
Dinan TG: Lithium augmentation in sertraline-resistant depression: a preliminary dose-response study. Acta Psychiatr Scand 88(4):300–301, 1993 8256650
Dinan TG, Kohen D: Tardive dyskinesia in bipolar affective disorder: relationship to lithium therapy. Br J Psychiatry 155:55–57, 1989 2575003
Dixon JF, Hokin LE: Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. Proc Natl Acad Sci U S A 95(14):8363–8368, 1998 9653192
Donaldson IM, Cuningham J: Persisting neurologic sequelae of lithium carbonate therapy. Arch Neurol 40(12):747–751, 1983 6625989
Donnelly EF, Goodwin FK, Waldman IN, Murphy DL: Prediction of antidepressant responses to lithium. Am J Psychiatry 135(5):552–556, 1978 645948
Dubovsky SL, Franks RD, Allen S: Verapamil: a new antimanic drug with potential interactions with lithium. J Clin Psychiatry 48(9):371–372, 1987 3114243
Dunner DL, Fieve RR: Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry 30(2):229–233, 1974 4589148
Dunner DL, Patrick V, Fieve RR: Rapid cycling manic depressive patients. Compr Psychiatry 18(6):561–566, 1977 923228
Emilien G, Maloteaux JM, Seghers A, Charles G: Lithium compared to valproic acid and carbamazepine in the treatment of mania: a statistical meta-analysis. Eur Neuropsychopharmacol 6(3):245–252, 1996 8880085
Engel T, Goñi-Oliver P, Lucas JJ, et al: Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 99(6):1445–1455, 2006 17059563
Fagiolini A, Buysse DJ, Frank E, et al: Tolerability of combined treatment with lithium and paroxetine in patients with bipolar disorder and depression. J Clin Psychopharmacol 21(5):474–478, 2001 11593071
Fagiolini A, Kupfer DJ, Scott J, et al: Hypothyroidism in patients with bipolar I disorder treated primarily with lithium. Epidemiol Psichiatr Soc 15(2):123–127, 2006 16865933
Fava M, Rosenbaum JF, McGrath PJ, et al: Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry 151(9):1372–1374, 1994 8067495
Fieve RR, Platman SR, Plutchik RR: The use of lithium in affective disorders. I. Acute endogenous depression. Am J Psychiatry 125(4):487–491, 1968 4886102
Findling RL, McNamara NK, Youngstrom EA, et al: Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 44(5):409–417, 2005 15843762
Findling RL, Robb A, McNamara NK, et al: Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study. Pediatrics 136(5):885–894, 2015 26459650
Finley PR, Warner MD, Peabody CA: Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 29(3):172–191, 1995 8521679
Finley PR, O’Brien JG, Coleman RW: Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 16(1):68–71, 1996 8834421
Fontaine R, Ontiveros A, Elie R, Vézina M: Lithium carbonate augmentation of desipramine and fluoxetine in refractory depression. Biol Psychiatry 29(9):946–948, 1991 1904782
Fountoulakis KN, Kasper S, Andreassen O, et al: Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. Eur Arch Psychiatry Clin Neurosci 262 (1 suppl 1):1–48, 2012 22622948
Frances A, Docherty JP, Kahn DA: Treatment of bipolar disorder. J Clin Psychiatry 57 (suppl):5–58, 1996
Franchini L, Zanardi R, Smeraldi E, Gasperini M: Early onset of lithium prophylaxis as a predictor of good long-term outcome. Eur Arch Psychiatry Clin Neurosci 249(5):227–230, 1999 10591987
Freeman MP, Stoll AL: Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 155(1):12–21, 1998 9433333
Freeman TW, Clothier JL, Pazzaglia P, et al: A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 149(1):108–111, 1992 1728157
Frye MA, Kimbrell TA, Dunn RT, et al: Gabapentin does not alter single-dose lithium pharmacokinetics. J Clin Psychopharmacol 18(6):461–464, 1998 9864078
Frye MA, Yatham LN, Calabrese JR, et al: Incidence and time course of subsyndromal symptoms in patients with bipolar I disorder: an evaluation of 2 placebo-controlled maintenance trials. J Clin Psychiatry 67(11):1721–1728, 2006 17196051
Garcia G, Crismon ML, Dorson PG: Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol 14(6):426–428, 1994 7884026
Garfinkel PE, Stancer HC, Persad E: A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. J Affect Disord 2(4):279–288, 1980 6450787
Geddes JR, Burgess S, Hawton K, et al: Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 161(2):217–222, 2004 14754766
Gelenberg AJ: Can lithium help to prevent suicide? (editorial). Acta Psychiatr Scand 104(3):161–162, 2001 11531652
Gelenberg AJ, Jefferson JW: Lithium tremor. J Clin Psychiatry 56(7):283–287, 1995 7615481
Gelenberg AJ, Kane JM, Keller MB, et al: Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 321(22):1489–1493, 1989 2811970
Geller B, Cooper TB, Sun K, et al: Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37(2):171–178, 1998a 9473913
Geller B, Cooper TB, Zimerman B, et al: Lithium for prepubertal depressed children with family history predictors of future bipolarity: a double-blind, placebo-controlled study. J Affect Disord 51(2):165–175, 1998b 10743849
Geller B, Luby JL, Joshi P, et al: A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry 69(5):515–528, 2012 22213771
Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ: Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry 42(2):196–199, 1997 9067070
Gitlin MJ, Cochran SD, Jamison KR: Maintenance lithium treatment: side effects and compliance. J Clin Psychiatry 50(4):127–131, 1989 2925600
Goldney RD, Spence ND: Safety of the combination of lithium and neuroleptic drugs. Am J Psychiatry 143(7):882–884, 1986 2872825
González RG, Guimaraes AR, Sachs GS, et al: Measurement of human brain lithium in vivo by MR spectroscopy. AJNR Am J Neuroradiol 14(5):1027–1037, 1993 8237676
Goodwin FK, Jamison KR: Manic Depressive Illness. New York, Oxford University Press, 1990
Goodwin FK, Zis AP: Lithium in the treatment of mania: comparisons with neuroleptics. Arch Gen Psychiatry 36(8 Spec No):840–844, 1979 36866
Goodwin FK, Murphy DL, Bunney WE Jr: Lithium-carbonate treatment in depression and mania. A longitudinal double-blind study. Arch Gen Psychiatry 21(4): 486–496, 1969 4896983
Goodwin FK, Murphy DL, Dunner DL, Bunney WE Jr: Lithium response in unipolar versus bipolar depression. Am J Psychiatry 129(1):44–47, 1972 4556087
Goodwin FK, Fireman B, Simon GE, et al: Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 290(11):1467–1473, 2003 13129986
Grahame-Smith DG: Disorder of synaptic homeostasis as a cause of depression and a target for treatment, in Antidepressant Therapy at the Dawn of the Third Millennium. Edited by Briley M, Montgomery S. London, Martin Dunitz, 1998, pp 111–140
Grandjean EM, Aubry JM: Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety. CNS Drugs 23(5):397–418, 2009 19453201
Granneman GR, Schneck DW, Cavanaugh JH, Witt GF: Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium. J Clin Psychiatry 57(5):204–206, 1996 8626351
Greenspan K, Schildkraut JJ, Gordon EK, et al: Catecholamine metabolism in affective disorders. 3. MHPG and other catecholamine metabolites in patients treated with lithium carbonate. J Psychiatr Res 7(3):171–183, 1970 5440858
Grünfeld JP, Rossier BC: Lithium nephrotoxicity revisited. Nat Rev Nephrol 5(5):270–276, 2009 19384328
Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ: Lithium treatment reduces suicide risk in recurrent major depressive disorder. J Clin Psychiatry 68(3):380–383, 2007 17388706
Haddjeri N, Szabo ST, de Montigny C, Blier P: Increased tonic activation of rat forebrain 5-HT(1A) receptors by lithium addition to antidepressant treatments. Neuropsychopharmacology 22(4):346–356, 2000 10700654
Hahn CG, Umapathy, Wang HY, et al: Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 39(4):355–363, 2005 16044535
Hajek T, Kopecek M, Höschl C, Alda M: Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 37(5):333–343, 2012 22498078
Hajek T, Bauer M, Simhandl C, et al: Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med 44(3):507–517, 2014 23721695
Heit S, Nemeroff CB: Lithium augmentation of antidepressants in treatment-refractory depression. J Clin Psychiatry 59 (suppl 6):28–33, discussion 34, 1998 9674934
Helmuth D, Ljaljevic Z, Ramirez L, Meltzer HY: Choreoathetosis induced by verapamil and lithium treatment. J Clin Psychopharmacol 9(6):454–455, 1989 2512332
Heninger GR, Charney DS, Sternberg DE: Lithium carbonate augmentation of antidepressant treatment. An effective prescription for treatment-refractory depression. Arch Gen Psychiatry 40(12):1335–1342, 1983 6418110
Himmelhoch JM, Neil JF, May SJ, et al: Age, dementia, dyskinesias, and lithium response. Am J Psychiatry 137(8):941–945, 1980 7416295
Ivkovic A, Stern TA: Lithium-induced neurotoxicity: clinical presentations, pathophysiology, and treatment. Psychosomatics 55(3):296–302, 2014 24388123
Jablensky AV, Morgan V, Zubrick SR, et al: Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. Am J Psychiatry 162(1):79–91, 2005 15625205
Jefferson JW: Lithium tremor and caffeine intake: two cases of drinking less and shaking more. J Clin Psychiatry 49(2):72–73, 1988 3338980
Jefferson JW, Greist JH: Primer of Lithium Therapy. Baltimore, MD, Williams & Wilkins, 1977
Jefferson JW, Greist JH, Ackerman DL: Lithium Encyclopedia for Clinical Practice. Washington, DC, American Psychiatric Press, 1983
Jermain DM, Crismon ML, Martin ES 3rd: Population pharmacokinetics of lithium. Clin Pharm 10(5):376–381, 1991 2049899
Joffe RT, Singer W, Levitt AJ, MacDonald C: A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry 50(5):387–393, 1993 8489327
Johnson G, Gershon S, Hekimian LJ: Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: an interim report. Compr Psychiatry 9(6):563–573, 1968 4883428
Johnson AG, Seideman P, Day RO: Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance. Drug Saf 8(2):99–127, 1993 8452660
Kantor D, McNevin S, Leichner P, et al: The benefit of lithium carbonate adjunct in refractory depression—fact or fiction? Can J Psychiatry 31(5):416–418, 1986 3089576
Karle J, Bjørndal F: [Serotonergic syndrome—in combination therapy with lithium and fluoxetine]. Ugeskr Laeger 157(9):1204–1205, 1995 7701669
Katona CLE, Abou-Saleh MT, Harrison DA, et al: Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine. Br J Psychiatry 166(1):80–86, 1995 7894881
Keck PE Jr, McElroy SL: Clinical pharmacodynamics and pharmacokinetics of antimanic and mood-stabilizing medications. J Clin Psychiatry 63 (suppl 4):3–11, 2002 11913673
Keck PE Jr, Mendlwicz J, Calabrese JR, et al: A review of randomized, controlled clinical trials in acute mania. J Affect Disord 59 (suppl 1):S31–S37, 2000 11121825
Keck PE Jr, Perlis RH, Otto MW, et al: The Expert Consensus Guideline Series: Treatment of bipolar disorder 2004. Postgrad Med Special Report (December):1–120, 2004
Keck PE, Orsulak PJ, Cutler AJ, et al; CN138-135 Study Group: Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord 112(1–3):36–49, 2009 18835043
Kessing LV, Forman JL, Andersen PK: Does lithium protect against dementia? Bipolar Disord 12(1):87–94, 2010 20148870
Kilts CD: In vivo imaging of the pharmacodynamics and pharmacokinetics of lithium. J Clin Psychiatry 61 (suppl 9):41–46, 2000 10826660
Kirov G: Thyroid disorders in lithium-treated patients. J Affect Disord 50(1):33–40, 1998 9716277
Kishimoto A: The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 16(4):483–493, 1992 1641493
Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 93(16):8455–8459, 1996 8710892
Kline NS: A narrative account of lithium usage in psychiatry, in Lithium: Its Role in Psychiatric Research and Treatment. Edited by Gershon S, Shopsin B. New York, Plenum, 1973, pp 5–24
Köhler S, Unger T, Hoffmann S, et al: Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. Pharmacopsychiatry 46(2):69–76, 2013 23093475
Kowatch RA, Suppes T, Carmody TJ, et al: Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 39(6): 713–720, 2000 10846305
Kulhara P, Basu D, Mattoo SK, et al: Lithium prophylaxis of recurrent bipolar affective disorder: long-term outcome and its psychosocial correlates. J Affect Disord 54(1–2):87–96, 1999 10403151
Kupka RW, Luckenbaugh DA, Post RM, et al: Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry 64(12):1483–1494, 2003 14728111
Kusalic M, Engelsmann F: Effect of lithium maintenance therapy on thyroid and parathyroid function. J Psychiatry Neurosci 24(3):227–233, 1999 10354657
Kushner SF, Khan A, Lane R, Olson WH: Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord 8(1):15–27, 2006 16411977
Lan CC, Liu CC, Lin CH, et al: A reduced risk of stroke with lithium exposure in bipolar disorder: a population-based retrospective cohort study. Bipolar Disord 17(7):705–714, 2015 26394555
Larsen ER, Damkier P, Pedersen LH, et al: Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl 132(445):1–28, 2015 26344706
Lauterbach E, Felber W, Müller-Oerlinghausen B, et al: Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand 118(6):469–479, 2008 18808400
Lazarczyk MJ, Giannakopoulos P: Temporal association as a prerequisite factor of valsartan-induced lithium toxicity. Bipolar Disord 16(6):662–666, 2014 24372930
Lee HC, Lin HC: Maternal bipolar disorder increased low birthweight and preterm births: a nationwide population-based study. J Affect Disord 121(1–2):100–105, 2010 19501914
Lejoyeux M, Ades J, Rouillon F: Serotonin syndrome: incidence, symptoms and treatment. CNS Drugs 2:132–143, 1994
Lemus CZ, Lieberman JA, Johns CA: Myoclonus during treatment with clozapine and lithium: the role of serotonin. Hillside J Clin Psychiatry 11(2):127–130, 1989 2488054
Lenox RH, McNamara RK, Watterson JM, Watson DG: Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain? J Clin Psychiatry 57 (suppl 13):23–31, discussion 32–33, 1996 8970502
Lepkifker E, Sverdlik A, Iancu I, et al: Renal insufficiency in long-term lithium treatment. J Clin Psychiatry 65(6):850–856, 2004 15291664
Lerer B, Moore N, Meyendorff E, et al: Carbamazepine versus lithium in mania: a double-blind study. J Clin Psychiatry 48(3):89–93, 1987 3546274
Levine J, Gonsalves M, Babur I, et al: Inositol 6 g daily may be effective in depression but not in schizophrenia. Hum Psychopharmacol 8(1):49–53, 1993
Levine J, Barak Y, Gonzalves M, et al: Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152(5):792–794, 1995 7726322
Lewitzka U, Severus E, Bauer R, et al: The suicide prevention effect of lithium: more than 20 years of evidence—a narrative review. Int J Bipolar Disord 3(1):32, 2015 26183461
Li X, Friedman AB, Zhu W, et al: Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder. Biol Psychiatry 61(2):216–222, 2007 16806104
Lombardi G, Panza N, Biondi B, et al: Effects of lithium treatment on hypothalamic-pituitary-thyroid axis: a longitudinal study. J Endocrinol Invest 16(4):259–263, 1993 8514981
Madhusoodanan S, Brenner R, Suresh P, et al: Efficacy and tolerability of olanzapine in elderly patients with psychotic disorders: a prospective study. Ann Clin Psychiatry 12(1):11–18, 2000 10798821
Maggs R: Treatment of manic illness with lithium carbonate. Br J Psychiatry 109:56–65, 1963
Malhi GS, Tanious M: Optimal frequency of lithium administration in the treatment of bipolar disorder: clinical and dosing considerations. CNS Drugs 25(4):289–298, 2011 21425882
Malhi GS, Tanious M, Das P, et al: Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs 27(2):135–153, 2013 23371914
Mani J, Tandel SV, Shah PU, Karnad DR: Prolonged neurological sequelae after combination treatment with lithium and antipsychotic drugs. J Neurol Neurosurg Psychiatry 60(3):350–351, 1996 8609524
Mann SC, Greenstein RA, Eilers R: Early onset of severe dyskinesia following lithium-haloperidol treatment. Am J Psychiatry 140(10):1385–1386, 1983 6624983
Markowitz GS, Radhakrishnan J, Kambham N, et al: Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 11(8):1439–1448, 2000 10906157
Martin CA, Piascik MT: First degree A-V block in patients on lithium carbonate. Can J Psychiatry 30(2):114–116, 1985 3922608
Massot O, Rousselle JC, Fillion MP, et al: 5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders. Neuropsychopharmacology 21(4): 530–541, 1999 10481837
McCrea RL, Nazareth I, Evans SJ, et al: Lithium prescribing during pregnancy: a UK primary care database study. PLoS ONE 10(3):e0121024, 2015 25793580
McKnight RF, Adida M, Budge K, et al: Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379(9817):721–728, 2012 22265699
Mekler G, Woggon B: A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 30(6):272–273, 1997 9442552
Mendels J: Lithium in the treatment of depressive states, in Lithium Research and Therapy. Edited by Johnson FN. New York, Academic Press, 1975, pp 43–62
Miller F, Menninger J, Whitcup SM: Lithium-neuroleptic neurotoxicity in the elderly bipolar patient. J Clin Psychopharmacol 6(3):176–178, 1986 2872237
Mirsepassi Z, Mazinani R, Fadai F, et al: Topiramate add-on lithium carbonate for treatment of acute mania. Iran J Psychiatry Behav Sci 7(2):11–15, 2013 24644505
Mitchell JE, Mackenzie TB: Cardiac effects of lithium therapy in man: a review. J Clin Psychiatry 43(2):47–51, 1982 7056703
Modell JG, Lenox RH, Weiner S: Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol 5(2):109–113, 1985 3988969
Mohammadianinejad SE, Majdinasab N, Sajedi SA, et al: The effect of lithium in post-stroke motor recovery: a double-blind, placebo-controlled, randomized clinical trial. Clin Neuropharmacol 37(3):73–78, 2014 24824661
Monti JM, Monti D, Jantos H, Ponzoni A: Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat. Neuropharmacology 34(12):1647–1651, 1995 8788962
Moore GJ, Bebchuk JM, Parrish JK, et al: Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. Am J Psychiatry 156(12):1902–1908, 1999 10588403
Moore GJ, Bebchuk JM, Wilds IB, et al: Lithium-induced increase in human brain grey matter. Lancet 356(9237):1241–1242, 2000 11072948
Muly EC, McDonald W, Steffens D, Book S: Serotonin syndrome produced by a combination of fluoxetine and lithium. Am J Psychiatry 150(10):1565, 1993 8379573
Netto I, Phutane VH: Reversible lithium neurotoxicity: review of the literature. Prim Care Companion CNS Disord 14(1), 2012 22690368
Newport DJ, Viguera AC, Beach AJ, et al: Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry 162(11):2162–2170, 2005 16263858
Nierenberg AA, Fava M, Trivedi MH, et al: A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 163(9):1519–1530, quiz 1665, 2006 16946176
Nierenberg AA, Friedman ES, Bowden CL, et al: Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium. Am J Psychiatry 170(1):102–110, 2013 23288387
Nierenberg AA, McElroy SL, Friedman ES, et al: Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. J Clin Psychiatry 77(1):90–99, 2016 26845264
Niufan G, Tohen M, Qiuqing A, et al: Olanzapine versus lithium in the acute treatment of bipolar mania: a double-blind, randomized, controlled trial. J Affect Disord 105(1–3):101–108, 2008 17531327
Nolen WA, Weisler RH: The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144). Bipolar Disord 15(1):100–109, 2013 23228201
Noyes R Jr, Dempsey GM, Blum A, Cavanaugh GL: Lithium treatment of depression. Compr Psychiatry 15(3):187–193, 1974 4826041
Oakley PW, Whyte IM, Carter GL: Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry 35(6):833–840, 2001 11990895
Ohman R, Spigset O: Serotonin syndrome induced by fluvoxamine-lithium interaction. Pharmacopsychiatry 26(6):263–264, 1993 8127934
Okuma T, Yamashita I, Takahashi R, et al. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 23(3):143–150, 1990 1973844
Patel NC, DelBello MP, Bryan HS, et al: Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry 45:289–297, 2006 16540813
Perényi A, Rihmer Z, Bánki CM: Parkinsonian symptoms with lithium, lithium-neuroleptic, and lithium-antidepressant treatment. J Affect Disord 5(2):171–177, 1983 6133888
Perényi A, Szücs R, Frecska E: Tardive dyskinesia in patients receiving lithium maintenance therapy. Biol Psychiatry 19(11): 1573–1578, 1984 6151403
Perlis RH, Sachs GS, Lafer B, et al: Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Am J Psychiatry 159(7):1155–1159, 2002 12091193
Peterson GA, Byrd SL: Diabetic ketoacidosis from clozapine and lithium cotreatment. Am J Psychiatry 153(5):737–738, 1996 8615434
Phiel CJ, Klein PS: Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 41:789–813, 2001 11264477
Phiel CJ, Wilson CA, Lee VM, Klein PS: GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423(6938):435–439, 2003 12761548
Poolsup N, Li Wan Po A, de Oliveira IR: Systematic overview of lithium treatment in acute mania. J Clin Pharm Ther 25(2): 139–156, 2000 10849192
Pope HG Jr, Cole JO, Choras PT, Fulwiler CE: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis 174(8):493–495, 1986 3090198
Popovic D, Reinares M, Goikolea JM, et al: Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol 22(5):339–346, 2012 22000157
Potkin SG, Thyrum PT, Bera R, et al: Open-label study of the effect of combination quetiapine/lithium therapy on lithium pharmacokinetics and tolerability. Clin Ther 24(11):1809–1823, 2002 12501876
Presne C, Fakhouri F, Noël LH, et al: Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int 64(2):585–592, 2003 12846754
Price LH, Charney DS, Heninger GR: Variability of response to lithium augmentation in refractory depression. Am J Psychiatry 143(11):1387–1392, 1986 3096155
Price LH, Charney DS, Delgado PL, Heninger GR: Lithium and serotonin function: implications for the serotonin hypothesis of depression. Psychopharmacology (Berl) 100(1):3–12, 1990 2404294
Prien RF, Caffey EM Jr, Klett CJ: Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry 26(2):146–153, 1972 4551257
Prien RF, Caffey EM Jr, Klett CJ: Prophylactic efficacy of lithium carbonate in manic-depressive illness. Report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry 28(3):337–341, 1973 4569674
Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK: Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 62(1):50–60, 2010 20453535
Reeves RR, Struve FA, Patrick G: Does EEG predict response to valproate versus lithium in patients with mania? Ann Clin Psychiatry 13(2):69–73, 2001 11534927
Reimers A, Skogvoll E, Sund JK, Spigset O: Drug interactions between lamotrigine and psychoactive drugs: evidence from a therapeutic drug monitoring service. J Clin Psychopharmacol 25(4):342–348, 2005 16012277
Rej S, Beaulieu S, Segal M, et al: Lithium dosing and serum concentrations across the age spectrum: from early adulthood to the tenth decade of life. Drugs Aging 31(12):911–916, 2014a 25331906
Rej S, Shulman K, Herrmann N, et al: Prevalence and correlates of renal disease in older lithium users: a population-based study. Am J Geriatr Psychiatry 22(11): 1075–1082, 2014b 24566239
Rej S, Yu C, Shulman K, et al: Medical comorbidity, acute medical care use in late-life bipolar disorder: a comparison of lithium, valproate, and other pharmacotherapies. Gen Hosp Psychiatry 37(6):528–532, 2015 26254672
Roose SP, Nurnberger JI, Dunner DL, et al: Cardiac sinus node dysfunction during lithium treatment. Am J Psychiatry 136(6):804–806, 1979 443464
Rosenqvist M, Bergfeldt L, Aili H, Mathé AA: Sinus node dysfunction during long-term lithium treatment. Br Heart J 70(4): 371–375, 1993 8217448
Ryan ND, Bhatara VS, Perel JM: Mood stabilizers in children and adolescents. J Am Acad Child Adolesc Psychiatry 38(5):529–536, 1999 10230184
Sachs GS, Rosenbaum JF, Jones L: Adjunctive clonazepam for maintenance treatment of bipolar affective disorder. J Clin Psychopharmacol 10(1):42–47, 1990a 2106533
Sachs GS, Weilburg JB, Rosenbaum JF: Clonazepam vs. neuroleptics as adjuncts to lithium maintenance. Psychopharmacol Bull 26(1):137–143, 1990b 1973545
Sachs GS, Vanderburg DG, Edman S, et al: Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 2: influence of protocol-specific eligibility criteria on signal detection. J Clin Psychiatry 73(11):1420–1425, 2012a 23218158
Sachs GS, Vanderburg DG, Karayal ON, et al: Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 73(11):1412–1419, 2012b 23218157
Sachs HC; Committee On Drugs: The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics 132(3):e796–e809, 2013 23979084
Sanger TM, Grundy SL, Gibson PJ, et al: Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study. J Clin Psychiatry 62(4):273–281, 2001 11379842
Saunders BD, Saunders EF, Gauger PG: Lithium therapy and hyperparathyroidism: an evidence-based assessment. World J Surg 33(11):2314–2323, 2009 19252941
Schaffer A, Isometsä ET, Tondo L, et al: Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. Aust N Z J Psychiatry 49(9):785–802, 2015 26185269
Schildkraut JJ, Logue MA, Dodge GA: The effects of lthium salts on the turnover and metabolism of norepinephrine in rat brain. Psychopharmacology (Berl) 14(2): 135–141, 1969 5350622
Schöpf J, Baumann P, Lemarchand T, Rey M: Treatment of endogenous depressions resistant to tricyclic antidepressants or related drugs by lithium addition. Results of a placebo-controlled double-blind study. Pharmacopsychiatry 22(5):183–187, 1989 2682692
Schou M: The effect of prophylactic lithium treatment on mortality and suicidal behavior: a review for clinicians. J Affect Disord 50(2–3):253–259, 1998 9858084
Schou M, Juel-Nielsen N, Stromgren E, Voldby H: The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 17(4):250–260, 1954 13212414
Schüle C, Baghai TC, Eser D, et al: Lithium but not carbamazepine augments antidepressant efficacy of mirtazapine in unipolar depression: an open-label study. World J Biol Psychiatry 10(4 Pt 2):390–399, 2009 18609420
Segal J, Berk M, Brook S: Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol 21(3):176–180, 1998 9617509
Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ: Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry 47(2):43–52, 2014 24549862
Severus WE, Lipkovich IA, Licht RW, et al: 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. Eur Psychiatry 25(8):443–449, 2010 20430594
Shahani L: Venlafaxine augmentation with lithium leading to serotonin syndrome. J Neuropsychiatry Clin Neurosci 24(3):E47, 2012 23037683
Shaldubina A, Agam G, Belmaker RH: The mechanism of lithium action: state of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry 25(4):855–866, 2001 11383981
Shao L, Young LT, Wang JF: Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells. Biol Psychiatry 58(11):879–884, 2005 16005436
Shine B, McKnight RF, Leaver L, Geddes JR: Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet 386(9992):461–468, 2015 26003379
Shopsin B, Gershon S, Thompson H, Collins P: Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Arch Gen Psychiatry 32(1):34–42, 1975 1089401
Shukla S, Godwin CD, Long LEB, Miller MG: Lithium-carbamazepine neurotoxicity and risk factors. Am J Psychiatry 141(12): 1604–1606, 1984 6439058
Shukla S, Cook BL, Miller MG: Lithium-carbamazepine versus lithium-neuroleptic prophylaxis in bipolar illness. J Affect Disord 9(3):219–222, 1985 2867109
Sipes TE, Geyer MA: Functional behavioral homology between rat 5-HT1B and guinea pig 5-HT1D receptors in the modulation of prepulse inhibition of startle. Psychopharmacology (Berl) 125(3):231–237, 1996 8815958
Small JG, Klapper MH, Milstein V, et al: Carbamazepine compared with lithium in the treatment of mania. Arch Gen Psychiatry 48(10):915–921, 1991 1929761
Small JG, Klapper MH, Marhenke JD, et al: Lithium combined with carbamazepine or haloperidol in the treatment of mania. Psychopharmacol Bull 31(2):265–272, 1995 7491378
Smith LA, Cornelius V, Warnock A, et al: Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord 9(6):551–560, 2007 17845269
Soares JC, Boada F, Spencer S, et al: Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T. Biol Psychiatry 49(5):437–443, 2001 11274655
Sobanski T, Bagli M, Laux G, Rao ML: Serotonin syndrome after lithium add-on medication to paroxetine. Pharmacopsychiatry 30(3):106–107, 1997 9211572
Spring GK: Neurotoxicity with combined use of lithium and thioridazine. J Clin Psychiatry 40(3):135–138, 1979 106047
Spring G, Frankel M: New data on lithium and haloperidol incompatibility. Am J Psychiatry 138(6):818–821, 1981 6113770
Spring G, Schweid D, Gray C, et al: A double-blind comparison of lithium and chlorpromazine in the treatment of manic states. Am J Psychiatry 126(9):1306–1310, 1970 4905019
Steckler TL: Lithium- and carbamazepine-associated sinus node dysfunction: nine-year experience in a psychiatric hospital. J Clin Psychopharmacol 14(5):336–339, 1994 7806689
Stein G, Bernadt M: Lithium augmentation therapy in tricyclic-resistant depression. A controlled trial using lithium in low and normal doses. Br J Psychiatry 162: 634–640, 1993 8149115
Stern DN, Fieve RR, Neff NH, Costa E: The effect of lithium chloride administration on brain and heart norepinephrine turnover rates. Psychopharmacology (Berl) 14(4):315–322, 1969 5350631
Stokes PE, Shamoian CA, Stoll PM, Patton MJ: Efficacy of lithium as acute treatment of manic-depressive illness. Lancet 1(7713):1319–1325, 1971 4103395
Stoll AL, Locke CA, Vuckovic A, Mayer PV: Lithium-associated cognitive and functional deficits reduced by a switch to divalproex sodium: a case series. J Clin Psychiatry 57(8):356–359, 1996 8752018
Stone KA: Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract 12(1):43–47, 1999 10050642
Stoudemire A, Moran MG, Fogel BS: Psychotropic drug use in the medically ill: Part I. Psychosomatics 31(4):377–391, 1990 2247565
Su Y, Ryder J, Li B, et al: Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43(22):6899–6908, 2004 15170327
Sugawara H, Sakamoto K, Harada T, Ishigooka J: Predictors of efficacy in lithium augmentation for treatment-resistant depression. J Affect Disord 125(1–3):165–168, 2010 20089312
Swann AC, Bowden CL, Morris D, et al: Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 54(1):37–42, 1997 9006398
Swanson CL Jr, Price WA, McEvoy JP: Effects of concomitant risperidone and lithium treatment (letter). Am J Psychiatry 152(7): 1096, 1995 7540798
Tajes M, Yeste-Velasco M, Zhu X, et al: Activation of Akt by lithium: pro-survival pathways in aging. Mech Ageing Dev 130(4):253–261, 2009 19162061
Takahashi R, Sakuma A, Itoh K, et al: Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Report of collaborative study group on treatment of mania in Japan. Arch Gen Psychiatry 32(10):1310–1318, 1975 1101844
Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN: The cardiovascular effects of lithium in man. A review of the literature. Am J Med 61(5):665–670, 1976 790953
Toffol E, Hätönen T, Tanskanen A, et al: Lithium is associated with decrease in all-cause and suicide mortality in high-risk bipolar patients: a nationwide registry-based prospective cohort study. J Affect Disord 183:159–165, 2015 26005778
Tohen M, Zarate CA Jr, Centorrino F, et al: Risperidone in the treatment of mania. J Clin Psychiatry 57(6):249–253, 1996 8666562
Tohen M, Greil W, Calabrese JR, et al: Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry 162(7):1281–1290, 2005 15994710
Tondo L, Jamison KR, Baldessarini RJ: Effect of lithium maintenance on suicidal behavior in major mood disorders. Ann N Y Acad Sci 836:339–351, 1997 9616808
Tondo L, Baldessarini RJ, Hennen J, Floris G: Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. Am J Psychiatry 155(5): 638–645, 1998 9585715
Tondo L, Hennen J, Baldessarini RJ: Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand 104(3): 163–172, 2001 11531653
Tredget J, Kirov A, Kirov G: Effects of chronic lithium treatment on renal function. J Affect Disord 126(3):436–440, 2010 20483164
Tsaltas E, Kontis D, Boulougouris V, et al: Enhancing effects of chronic lithium on memory in the rat. Behav Brain Res 177(1):51–60, 2007 17141335
Vieta E, T’joen C, McQuade RD, et al: Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry 165(10):1316–1325, 2008 18381903
Viguera AC, Nonacs R, Cohen LS, et al: Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 157(2):179–184, 2000 10671384
Viguera AC, Newport DJ, Ritchie J, et al: Lithium in breast milk and nursing infants: clinical implications. Am J Psychiatry 164(2):342–345, 2007a 17267800
Viguera AC, Whitfield T, Baldessarini RJ, et al: Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 164(12):1817–1824, quiz 1923, 2007b 18056236
Vita A, De Peri L, Sacchetti E: Lithium in drinking water and suicide prevention: a review of the evidence. Int Clin Psychopharmacol 30(1):1–5, 2015 25025988
Vollmer KO, von Hodenberg A, Kölle EU: Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittelforschung 36(5):830–839, 1986 3730018
Ward ME, Musa MN, Bailey L: Clinical pharmacokinetics of lithium. J Clin Pharmacol 34(4):280–285, 1994 8006194
Wehr TA, Sack DA, Rosenthal NE, Cowdry RW: Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry 145(2):179–184, 1988 3341463
Weisler RH, Nolen WA, Neijber A, et al; Trial 144 Study Investigators: Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry 72(11):1452–1464, 2011 22054050
Williams RS, Harwood AJ: Lithium therapy and signal transduction. Trends Pharmacol Sci 21(2):61–64, 2000 10664610
Wright BA, Jarrett DB: Lithium and calcium channel blockers: possible neurotoxicity. Biol Psychiatry 30(6):635–636, 1991 1932412
Yildiz A, Vieta E, Leucht S, Baldessarini RJ: Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 36(2):375–389, 2011 20980991
Yoshida S, Maeda M, Kaku S, et al: Lithium inhibits stress-induced changes in tau phosphorylation in the mouse hippocampus. J Neural Transm (Vienna) 113(11):1803–1814, 2006 16855914
Young AH, McElroy SL, Bauer M, et al; EMBOLDEN I (Trial 001) Investigators: A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 71(2):150–162, 2010 20122369
Zarate CA, Manji HK: Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 23(7):569–582, 2009 19552485
Zusky PM, Biederman J, Rosenbaum JF, et al: Adjunct low dose lithium carbonate in treatment-resistant depression: a placebo-controlled study. J Clin Psychopharmacol 8(2):120–124, 1988 3131389