Lithium in the Treatment of Bipolar Disorder
Christian Jonathan Haverkampf, M.D.
Lithium is one of the most widely used and studied medications for treating bipolar disorder. It helps reduce the severity and frequency of mania and may also help relieve or prevent bipolar depression. Studies have also shown that lithium can significantly reduce suicide risk and helps to prevent future manic and depressive episodes. As a result, it is usually prescribed as maintenance therapy for longer periods of time. However, the occurrence of side effects can in several cases lead to its discontinuation and reduce compliance.
Keywords: lithium, bipolar disorder, medication, treatment, psychiatry
Table of Contents
Reducing Excitatory Signals and Increasing Inhibitory Signals. 10
Neurotransmission Modulation. 10
Lithium vs Atypical Antipsychotics. 16
Lithium vs Other Mood Stabilizers. 17
Introduction
Bipolar disorder is a prevalent, costly and life-threatening illness, characterized by mood swings between (hypo)manic states and depression, interspersed with normal mood. It is is among the 10 most disabling medical conditions worldwide, causing huge individual suffering, losses of relationships and missed opportunities, and significant economic loss to society overall.
Lithium has been the major mood-stabilizing treatment for the disorder for 50 years. More recently, drugs developed for other illnesses have proved useful as mood stabilizers, including the anticonvulsants valproate and lamotrigine, and various, predominantly second generation, antipsychotics.
Antidepressant drugs are often used to treat depressive episodes, but they are usually given together with a mood stabilizer because they can destabilize the illness or precipitate a manic episode. Giving a patient with bipolar disorder an antidepressant alone should be avoided because it could trigger a (hypo)manic episode, particularly if it is one of the more activating one.
Since the quality of life and the compliance depend to a significant degree on the trade-off between a drug’s positive effects and side-effects, the generally higher side effects of mood stabilizers as compared to modern antidepressants also more frequently lead to discontinuation of a drug by the patient, particularly if the prescriber does not provide enough information about the drug.
Heritability
Bipolar disorder is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells.
Lithium
Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer and has a wealth of empirical evidence supporting its efficacy in this role. However, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment.
Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis, while the evidence for its efficacy in depression is only modest. In a study with 802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II), Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium, on the other hand, did not significantly differ from placebo on the main measures of efficacy. (Young et al., 2010)
However, lithium seems to be more effective when used to augment the effect of an antidepressant. In a systematic search of Medline and the Cochrane Clinical Trials database adjunctive lithium appeared to be as effective for second generation antidepressants as it was for the tricyclics. The odds ratio for response to lithium vs. placebo in all contrasts combined was 2.89. It was effective with TCAs (7 contrasts) and with second generation agents (3 contrasts). Discontinuation due to adverse events was infrequent and did not differ between lithium and placebo. (Nelson, Baumann, Delucchi, Joffe, & Katona, 2014) In another comprehensive database search, augmentation of SSRIs with lithium or second generation antipsychotics was likely to be beneficial in people with treatment resistant depression. Clinical evaluation based on the limited evidence identified in the research indicated no statistically significant difference between the two augmentation strategies. Cost-effectiveness analyses suggested that augmentation with lithium was less expensive and more effective than augmentation with the second generation antipsychotic. (Edwards, Hamilton, Nherera, & Trevor, 2013)
Lithium possesses unique anti-suicidal properties that set it apart from other agents. s Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders. Lithium may exert its antisuicidal effects by reducing relapse of mood disorder, but additional mechanisms should also be considered because there is some evidence that lithium decreases aggression and possibly impulsivity, which might be another mechanism mediating the antisuicidal effect. (Cipriani, Hawton, Stockton, & Geddes, 2013) The anti-inflammatory effects of lithium result from its inhibition of glycogen synthase kinase-3 (GSK3), and GSK3 has been demonstrated to strongly promote inflammation, aggressive behavior in rodents and depression-like behaviors in rodents. Stress may thus activate GSK3, which in turn promotes inflammation, which may be linked to behaviors associated with suicide, including particularly aggression, impulsivity and depression. (Beurel & Jope, 2014)
Patients with bipolar I disorder tend to have verbal memory deficits that are not explained by medication or by lithium monotherapy, but by the condition itself (López-Jaramillo et al., 2010) With respect to cognition, studies suggest that lithium may even reduce cognitive decline in patients (Malhi, Tanious, Das, Coulston, & Berk, 2013). In one study of 54 patients assessed at baseline and six years later, executive functioning, inhibition, processing speed and verbal memory were impaired in euthymic bipolar out-patients. Although cognitive deficits remained stable on average throughout the follow-up, they had enduring negative effects on psychosocial adaptation of patients. (Mora, Portella, Forcada, Vieta, & Mur, 2013)
Bipolar Disorder
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression, and without treatment, 15% of patients commit suicide. It affects more than 1% of the world’s population irrespective of nationality, ethnic origin, or socioeconomic status(Grande, Berk, Birmaher, & Vieta, 2016). It is thus a condition which is associated with high morbidity and, according to the World Health Organization, with a significant loss in productivity. Bipolar disorder is responsible for the loss of more disability-adjusted life-years than all forms of cancer or major neurologic conditions such as epilepsy and Alzheimer disease (Organization, 2002), primarily because of its early onset and chronicity across the life span. Despite cross-site variation in the prevalence rates of bipolar disorder, the severity, impact, and patterns of comorbidity are remarkably similar internationally (Merikangas et al., 2011).
Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics (Geddes & Miklowitz, 2013). SIgnificant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN, and strong evidence exists for a polygenic contribution to risk (Craddock & Sklar, 2013). However, genomic structural variations seem to play a smaller role in bipolar disorder as compared with schizophrenia, for example.
The current understanding of the neurobiology of bipolar disorder has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of bipolar disorder (Berk et al., 2011). Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission.
Mechanism
There are two major candidate target proteins for lithium’s primary therapeutic action
- inositol monophosphatase (IMPase)
- glycogen synthase kinase-3 (GSK-3)
IMPase is encoded by the gene IMPA-14, whose mRNA is enriched in neuronal axons. IMPase-1 and GSK-3 are inhibited at therapeutic lithium levels of 0.4–1 mEq/L.
GSK3β Inhibition
Malhi and Outhred conducted a literature search using the Scopus database from 2012). Recent research has further reaffirmed glycogen synthase kinase 3β (GSK3β) inhibition as a key mechanism, and the inter-associations between GSK3β-mediated neuroprotective, anti-oxidative and neurotransmission mechanisms have been further elucidated. (Malhi & Outhred, 2016)
IMPase Inhibition
One proposal has been that lithium’s ability to inhibit the enzyme inositol monophosphatase (IMPase) reduces the supply of recycled inositol used for membrane phosphoinositide (PIns) synthesis. Inhibition is only seen when IMPase’s substrate, IP1, accumulates. This suggests a mechanism in which lithium inhibition would be confined to neurons with high rates of PIns turnover, giving it selectivity for certain brain areas.
Saiardi and Mudge used mature cultured cortical neurons to show that, although lithium has little effect on steady-state levels of either inositol or PIns, it markedly inhibits the rate of PIns synthesis, and that rapid synthesis of membrane PIns preferentially uses inositol newly imported from the extracellular space. Interestingly, the antidepressant fluoxetine stimulates the rate of PIns synthesis, and has thereby the opposite effect on this biological mechanism as compared to the mood stabilizer lithium. (Saiardi & Mudge, 2018)
Reducing Excitatory Signals and Increasing Inhibitory Signals
While lithium reduces excitatory neurotransmission (dopamine and glutamate) and increases inhibitory neurotransmission (GABA) on the synaptic level, this cannot be necessarily translated into a system-wide effect as autoregulatory mechanisms among the neurotransmission systems and neural networks could counteract this effect (Haverkampf, 2018).
Neurotransmission Modulation
Lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission.
Neuroprotection
The neuroprotective properties of lithium may also contribute to the therapeutic effect. Lithium has been shown to reduce the oxidative stress that occurs in the course of multiple episodes of mania and depression. It also increases protective proteins such as brain-derived neurotrophic factor (BDNF) and BCL-2, and reduces apoptotic processes through inhibition of GSK-3 and autophagy.
Lithium also appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects.
Positive Effects
Lithium is used primarily for long-term treatment of bipolar disorder with the aim to prevent further manic and depressive recurrences. In this indication, lithium remains a first-line treatment. It is also the only medication that has demonstrated an antisuicidal effect. However, it must be remembered at the same time that, while lithium can also soften the depressive episode, it is not an antidepressant and does not have their effectiveness against depression.
In mice, reduced dopamine transporter levels improved reversal learning and motivation. Chronic lithium alone impaired probabilistic learning in mice. Lithium remediated behavioral effects of reduced dopamine transporter levels. Lithium exerted only main, not synergistic effects, on neurotransmitter levels. (Milienne-Petiot et al., 2017)
Lithium has proven useful in major depression, particularly for augmentation of antidepressants and against aggressive behavior, aside from the mentioned antisuicidal effect. With respect to the antisuicidal effect, lithium also reduces the risk in patients who otherwise do not respond to the mood stabilizing effect.
Side Effects
About half of all individuals may stop their treatment at some point, despite lithium’s proven benefits. The main reason is the frequent occurrence of side effects. Most of the reported side effects probably do not pose relevant risks to a patient’s physical health, but they can become untenable on an individual level. These may include everything from increased thirst, sedation, not feeling good to increased appetite and weight gain, which can then also cause additional health risks. In clinical practice, milder gastrointestinal side effects or sedation often go away over a few weeks.
A retrospective cohort study in the Swedish region of Norrbotten into the causes of lithium discontinuation between 1997 and 2013 revealed that 54% discontinued lithium (Öhlund et al., 2018). The five single most common adverse effects leading to lithium discontinuation were diarrhoea (13%), tremor (11%), polyuria/polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%). Interestingly, although women were as likely as men to take the initiative to stop lithium, they were twice as likely to consult a doctor before actually stopping the medication. (Öhlund et al., 2018)
Lithium treatment does not seem to be associated with an increased incidence of cancer. Martinsson and colleagues found an increased risk of respiratory, gastrointestinal, and endocrine cancer in patients with bipolar disorder without lithium treatment. (Martinsson, Westman, Hällgren, Ösby, & Backlund, 2016)
Lithium can have several side effects, some of them potentially severe and even lethal. It is always important to consult the literature before prescribing lithium in a specific case.
Lithium vs Atypical Antipsychotics
In a randomized study on patients with bipolar I or II disorder taking lithium (n = 240) or quetiapine (n = 242), both with adjunctive therapy, participants improved across all measures, and over 20% had a sustained response. Primary and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine. Among those with anxiety, the lithium group had fewer necessary clinical adjustments per month. Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency, intensity, and impairment. Outcomes with lithium and quetiapine were not significantly different across 6 months of treatment for bipolar disorder. (Nierenberg et al., 2016)
Lithium vs Other Mood Stabilizers
As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, Kessing and colleagues undertook a systematic literature search of non‐randomized controlled observational studies. In eight out of nine identified studies including a total of near 14,000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of more than 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not. (Kessing et al., 2018)
Treatment-Resistance
Bipolar disorder, similar to other psychiatric conditions, is a product of diverse changes in a complex neural network. Although, it can be a consequence of relatively narrowly definable biomolecular processes, the immediate alterations and the symptoms it causes are often varied and manifold. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in bipolar disorder.
Developmental Variations
Several induced pluripotent stem cell (iPSC) lines from patients and healthy controls have been investigated. Early studies suggest differences in activity, calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Impairment in the differentiation of patient-derived neurons to dorsal telencephalic derivatives has been observed. Possible explanations are alterations in WNT, Hedgehog or Nodal pathway signaling. (O’Shea & McInnis, 2016)
Hyperexcitability is one early endophenotype of bipolar disorder. Focusing on hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Mertens and colleagues have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays and, using both patch-clamp recording and somatic Ca2+ imaging, they have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. (Mertens et al., 2015)
Disclosure
The author reports no conflicts of interest in this work.
Dr Jonathan Haverkampf, M.D. MLA (Harvard) LL.M. trained in medicine, psychiatry and psychotherapy, law and economics. He works in private practice for psychotherapy, counselling and psychiatric medication in Dublin, Ireland. Jonathan is the author of over two hundred articles and several books. He can be reached by email at jo****************@gm***.com or on the websites www.jonathanhaverkampf.com and www.jonathanhaverkampf.ie.
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