ORIGINAL ARTICLE

Litiul – o opţiune terapeutică necesară în tulburările afective

 Lithium – a necessary therapeutic option for affective disorders

First published: 06 septembrie 2022

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Psih.70.3.2022.6976

Abstract

Bipolar affective disorder (BD) affects 1 in 100 people worldwide, with a 10- to 20-fold higher risk of suicide in untreated individuals compared to the general population. An effective therapeutic approach in bipolar affective disorder depends on a clinical and anamnestic exploration as complex as possible regarding the factors involved, for a correct specification of the diagnosis, which must be corroborated, as far as possible, with good therapeutic compliance. Lithium carbonate, derived from lithium metal, discovered more than 70 years ago by Australian psychiatrist John Cade, is still the standard, first-line treatment for bipolar affective disorders. Since the psychotropic medication currently used in BD therapy has, in addition to the beneficial effects, certain side effects, the treatment of the manic episode continues to be a topic of interest in medical research, viewed from the perspective of increasing patient’s compliance to treatment and finding the ideal mood stabilizer, as well as some predictors of therapeutic response. Unfortunately, lithium carbonate has not been available for many years in Romania, which deprives patients with mental disorders of a formidable first-line pharmacotherapeutic tool, that is widely used in Europe and around the world.
 

Keywords
lithium, affective disorder, mood stabilizer, treatment

Rezumat

Tulburarea afectivă bipolară (TAB) afectează 1 din 100 de persoane în întreaga lume, cu un risc suicidar de 10 până la de 20 de ori mai mare în cazul persoanelor netratate, comparativ cu populaţia generală. Un demers terapeutic eficient în tulburarea afectivă bipolară depinde de o explorare clinică şi anamnestică foarte complexă privind factorii implicaţi, pentru o precizare corectă a diagnosticului, ce trebuie coroborată, pe cât posibil, cu o bună complianţă terapeutică. Carbonatul de litiu, derivat din metalul de litiu, descoperit de peste 70 de ani de psihiatrul australian John Cade, este în continuare tratamentul standard, de primă linie, pentru tulburările afective bipolare. Întrucât medicaţia psihotropă utilizată în prezent în terapia TAB are, pe lângă efectele benefice, şi anumite reacţii adverse, tratamentul episodului maniacal reprezintă în continuare un subiect de interes al cercetării medicale, privit prin prisma creşterii complianţei pacienţilor la tratament şi a găsirii normostabilizatorului ideal, precum şi a unor factori de predicţie a răspunsului terapeutic. Din nefericire, carbonatul de litiu nu este disponibil de mulţi ani în România, fapt ce privează pacienţii cu tulburări psihice de un redutabil instrument farmacoterapeutic de primă linie şi care este utilizat pe scară largă în Europa şi în lume.
 

Introduction

Among all mental disorders, affective disorders have been subjected, over time, to the widest nosological reconsiderations, as a result of relevant discoveries in the field of etiology, from a biochemical and genetic perspective. Also, the progress in the field of clinical-psychological knowledge is noteworthy, through the development of structured interviews and specifically calibrated scales, which allow a thorough deepening and as faithful a quantification of clinical phenomena as possible(1).

Bipolar affective disorder (BD) is characterized by repeated episodes (at least two) in which the patient’s mood and activity levels are significantly disrupted, in some cases consisting of euphoric mood and increased energy and activity (mania and hypomania), and in others, of depressive mood, with decreased energy and activity (depression). Affective disorders have an episodic evolution, with important personal, family and social implications, and they were identified, described and recorded before the other mental illnesses. The main nosographic entities of affective psychoses – mania and melancholia – were described by Hippocrates as early as the 4th century BC(2).

The high morbidity due to affective disorders, and especially the depressive ones, determined the creation, in 1975, of an International Committee for the Prevention and Treatment of Depressions which periodically publishes information bulletins on the epidemiological and clinical data related to this mental disorder. Epidemiological research has reported for type I bipolar disorder a prevalence between 0.4% and 1.6%, while type II bipolar disorder is frequently underdiagnosed due to the difficulties in recognizing the hypomanic symptomatology and differentiating it from the induced manic turn by antidepressant medication. Therefore, the prevalence of type II BD is considered higher than 1.6%. In this context, it is estimated that the “real” prevalence of bipolar disorder is estimated at 5% of the general population(1,3).

Among the risk factors of affective disorders, which influence the incidence, prevalence and risk of illness, are sex, age, marital status, socioeconomic level, geographical area and the urban/rural environment. Bipolar affective disorder, defined according to the specific diagnostic criteria of diagnostic manuals, still remains a heterogeneous nosological category, which would require a subdivision into different subgroups, depending on biological and psychopharmacological aspects. The correct choice of the ideal stabilizer for the treatment of patients diagnosed with BD is still a challenge for clinicians.

A clear, complete definition of a mood stabilizer is difficult to achieve, but in the strictest way it is considered that it should have antimanic, antidepressant and prophylactic action. Thus, regarding the treatment of BD, lithium remains the only mood stabilizer that meets all these requirements and the first therapeutic option, although there are other drugs that can be used and have the role of mood stabilizer(4). Lithium is a conventional mood stabilizer with a slower onset of action than antipsychotics.

The use of lithium in medicine dates back about 160 years and, initially, it was used in the treatment of gout. In 1949, Cade published an article in the Medical Journal of Australia in which he highlighted the rapid improvement of symptomatology in 10 patients with mania treated with lithium carbonate. This experiment was carried out after Cade tested the tranquilizing effects of lithium on himself. However, his article went unnoticed by the scientific community and, therefore, in 1950, Cade abandoned his experiments. Later, the Danish psychiatrist Poul Baastrup replicated the experiments with lithium, under much stricter conditions than Cade, and in 1970 he published in The Lancet the results of a double-blind, placebo-controlled study which highlighted the effect of lithium in the BD therapy.

Mechanism of action

Lithium has a complex mechanism of action, although it is a monovalent cation, but with a wide cellular and tissue distribution. Most clinical studies in preclinical or clinical models support its neuroprotective role. Thus, it offers a wide spectrum of clinical use, but also various adverse effects. Future research may focus on understanding the important neurotrophic effects of lithium by studying lithium-responsive gene networks linked to this trophic effect. Also, a better response to lithium therapy can be obtained, considering the therapeutic limitations related to its plasma concentration, by studying the biological predictors of the therapeutic response. Currently, there are already a number of biological predictors of response to lithium therapy in BD. Among these, special attention is given to various biochemical measurements correlated with the neurobiological responsiveness of lithium therapy in BD. These predictors are represented by low levels of IMP-ase mRNA, low brain intracellular pH, and calcium ion response(4).

Lithium has an important neurotrophic effect, as indicated by imaging studies showing the association between lithium therapy and the increased brain gray matter volume related to emotional and cognitive processes, such as the cingulate gyrus, amygdala or hippocampus. Thus, an MRI imaging study, carried out by Sassi, which included patients diagnosed with BD, of which 17 treated with lithium and 12 without treatment with lithium, who were compared with a control group, consisting of 46 people, without the diagnosis of BD, highlights the fact that the volume of cerebral gray matter is much increased in patients treated with lithium compared to the other two groups(14,15).

Efficacy

Lithium is associated with a slight improvement in symptoms in 40% to 80% of patients after two to three weeks of treatment in the manic episode(5,6).

Lithium balances mood swings in both directions, from mania to depression and from depression to mania, so it is not only used for manic episodes, but has also proven effective as a long-term maintenance treatment for bipolar disorder(6). Lithium can reduce severe manic symptoms within about 5 to 14 days after starting therapy. With regular monitoring, lithium is a safe and effective medication that allows many people diagnosed with bipolar affective disorder to live normal lives(6).

There is a significant number of patients who do not respond or have a partial response to lithium therapy. Therefore, an attempt was made to find some psychopathological predictors that would assess the response of patients to lithium therapy. The factors showing a positive response to lithium therapy are represented by the reduced number of affective episodes existing in the evolution of BD, an evolutionary clinical model of mania-depression type, family antecedents of affective disorder, and the existence of euphoric mood. Factors of poor response to lithium therapy are represented by the mixed episode, the existence of psychotic symptomatology associated with affective episodes, rapid cycling, association with the abuse of alcohol or other psychoactive substances(4). The need for gradual titration of the lithium dose is important to reduce drug toxicity, but this action may lead to a delay in therapeutic response.

A study conducted in Malaysia aimed to evaluate the efficacy and tolerability of lithium and to determine the factors associated with a response to lithium therapy among patients diagnosed with bipolar affective disorder. The retrospective study was conducted in a tertiary care hospital in Malaysia, which included 47 patients with bipolar disorder who were prescribed lithium maintenance therapy between January 2009 and December 2013. Of all the baseline characteristics tested, only the presence of psychotic patients differentiated lithium monotherapy from combination treatment. The discontinuation of lithium maintenance treatment occurred in only five cases with adverse effects. Depressive episode occurring before lithium treatment and during the first interval of lithium maintenance treatment significantly predicted the treatment response to lithium therapy(7).

Currently, the accepted therapeutic range is 0.6-1 mmol/L, the lower values being suitable for prophylaxis in elderly patients as well, and the higher values being used in the acute treatment and prophylaxis of unstable bipolar affective disorders. Today, lithium is widely used in the prophylaxis and treatment of mania and hypomania, recurrent depression and bipolar affective disorders in general(10,11).

A 2009 report by the National Institute for Health and Clinical Excellence in England indicated a stable use of lithium from 2000 to 2009, being considered a well-established drug among clinicians, although the other mood stabilizer drugs are heavily publicized by the pharmaceutical industry and only apparently there is an increase in their use(12).

Recent therapeutic guidelines recommend the use of lithium as the first option for the treatment of classic manic episode, although some authors recommend it only for mild forms. Its association with other mood stabilizer drugs is recommended by all guidelines. Also, the WFSBP guideline (The World Federation of Societies of Biological Psychiatry) recommends it as monotherapy only if the long-term maintenance therapy is indicated. Lithium remains the first line of treatment for the depressive episode in bipolar disorder. However, due to conflicting evidence, the WFSBP guideline has a grade 5 recommendation – a low recommendation – but remains as a first choice due to the few therapeutic options currently available for bipolar depression(12,13).

Regarding maintenance therapy, lithium is also the first therapeutic option, according to the indications of all therapeutic guidelines. There are numerous clinical trials supporting its effectiveness as an anti-suicide agent. Lithium is used in maintenance therapy when it has also been used in the acute phase of mania. It is used alone or combined with other drugs with a mood stabilizer role, in the continuation of the acute phase, after its remission, but it can also be added later in the treatment scheme, if it was not used from the beginning. Thus, lithium remains a drug of choice in the long-term maintenance therapy, but this therapeutic option can be changed, if another mood stabilizer was used in the acute phase and symptom remission was obtained, the patient prefers a drug other than lithium or the one previously used did not have the expected answer. Additionally, lithium is used if there is a family history of BD, complete interepisodic remission, and affective episodes with typical, classic symptomatology(12).

Indications

The main indications of lithium salts(9,10) recognized today are:

  • prophylaxis and maintenance treatment in bipolar affective disorder;

  • treatment of the manic episode;

  • preventing or reducing the intensity of recurrent manic or depressive episodes;

  • potentiation of the antidepressant effect in depressive and obsessive-compulsive disorders;

  • secondary affective disorders from psychoorganic syndromes;

  • antisocial/aggressive behavior;

  • migraine headache;

  • general medicine – spasmodic torticollis, thyrotoxicosis, Meniere’s vertigo, blood dyscrasias (neutropenia).

  • For the use of lithium and lithium salts(8-10), the following specifications are necessary:

  • the initiation of treatment will not be done at the level of primary care;

  • the initiation of the treatment will be done under conditions of hospitalization and monitoring, requiring the patient and relatives to be informed of the fact that it is a long-term treatment with risks that will be outlined, and for their prevention, good quality therapeutic compliance is needed, insisting on monitoring the blood level of lithium;

  • lithium monitoring, the normal value being 0.6-0.8 mmol/L;

  • additional monitoring – thyroid function, sodium reserve, renal function (urea, creatinine);

  • it must not be associated with acetylcholinesterase inhibitors, diuretics and nonsteroidal anti-inflammatory substances;

  • the diarrheal syndrome can be the first sign of the neurotoxic syndrome induced by lithium, associating paresthesia, ataxia, tremors and alteration of the state of cognition, confusional episodes; the neurological signs of neurotoxic syndrome require permanent evaluation;

  • the appearance of the neurotoxic syndrome, even the “sketch of the neurotoxic syndrome”, requires the discontinuation of medication and specialized assistance under hospitalization conditions;

  • the patient and his family will be informed and will alert the medical team under conditions of long-term lithium treatment when the patient presents with diarrhea, vomiting or a change in his neurological status; good hydration is required during the therapy period, avoiding medium-term immobilization or the presence of an infectious state (e.g., pneumonia accompanied by fever and profuse sweating);

  • lithium treatment must be reevaluated in any situation where a medical condition requires another specific medication.

Contraindications

In 1977, an article was published wich showed that the long-term treatment with lithium can induce mild but irreversible chronic kidney damage with decreased renal filtration capacity. Thus, the use of lithium in psychiatry experienced a slight decline, its administration being done with a higher degree of caution(8,9). Later, the renal toxicity of lithium salts in sodium-depleted patients was discovered, which led to the introduction of standardized lithium testing.

The contraindications to lithium treatment stem primarily from its long-term toxicity, given the indefinite duration of maintenance treatment. The most common contraindications(8-10) are:

  • kidney or liver failure;

  • cardiovascular disorders;

  • association with electroconvulsive therapy;

  • the association with some neuroleptics (e.g., haloperidol) may increase the risk of neurotoxicity.

Adverse effects

The adverse effects coincide with the peak of lithium concentration and appear probably due to the rapid absorption of the lithium ion, disappearing in a few weeks. These(9,10) are:

  • gastrointestinal irritation (nausea, abdominal pain, diarrhea);

  • muscle fatigue, fatigue, dysarthria, blurred vision, vertigo;

  • fine tremor of the extremities, weight gain, polyuria, polydipsia, edema;

  • headache, skin rashes, exacerbation of psoriasis, acne, itching, sexual dysfunctions, hyperglycemia, anemia, dizziness;

  • long-term – kidney damage, hypothyroidism, hyperparathyroidism with hypercalcemia.

The important adverse effects of lithium, consi­dered severe, potentially irreversible, and of concern to clinicians, include renal manifestations or CNS toxicity. In addition, weight gain or adverse effects such as cognitive impairment can be added, which worry some patients. There is also a teratogenic risk, but this is relatively low(12).

Recommendations for the use of lithium in the international guidelines

The recommendations of the therapeutic guidelines for the treatment of BD, from the last 10 years, according to the level of evidence and recommendation of the therapeutic line for the manic episode in the case of the use of lithium, are the following(5):

1. CANMAT (Canadian Network for Depressive and Anxiety Disorders)

Evidence level = 1.

Therapeutic line =1.

2. WFSBP – manic episode with mixed features

Level of evidence = inadequate information (monotherapy/therapeutic combinations).

Therapeutic line = 3/5 (treatment/prevention of manic episode/acute mixed).

3. CINP (International College of Neuropsycho­pharmacology)

Evidence level = 2.

4. RANZCP (Royal College of Psychiatrists of Australia and New Zealand)

Evidence level = 1.

Thus, lithium joined the antidepressants and neuroleptics that achieved the so-called psychopharmacological revolution of the 1950s(16).

Bipolar affective disorder affects 1 in 100 people worldwide, with a 10- to 20-fold higher risk of suicide in untreated individuals compared to the general population(16).

We observe from the evidence provided by the specialized literature and from the main guidelines that there are no counterarguments for replacing lithium with other drugs. The reality of the last years shows us that in some countries the use of lithium has even increased or remained at high levels. In some European countries, there are over 50% of patients with bipolar disorder receiving lithium treatment versus 17% in the United States of America(17).

A recently published study surveying a substantial group of Spanish psychiatrists shows that 70% of them prescribed lithium to more than 50% of patients diagnosed with bipolar disorder, and 1 in 5 prescribed lithium to more than 75% of patients. Moreover, 75% of the psychiatrists who participated in this study chose lithium as the treatment of first choice in the maintenance phase of bipolar disorder in both sexes(17). The high percentage of lithium use by Spanish psychiatrists would be consistent with the recent prescription in The Netherlands, where 70% of the patients with bipolar or schizoaffective disorder received lithium treatment(18). Despite solid clinical evidence and first-line recommendations, we must emphasize that this percentage is significantly higher than in other neighboring countries(19), which nevertheless benefit from lithium treatment, unlike Romania, where it has not been available for decades. For example, in Sweden, the prescription rate for lithium in BD is 55%(20), in Denmark it is 41.7%(21), and in Germany – 26.2%(22).

In synthesis, lithium carbonate, derived from lithium metal, discovered more than 70 years ago by Australian psychiatrist John Cade, is still the standard, first-line treatment for bipolar affective disorders, available and prescribed worldwide.

Unfortunately, lithium carbonate has not been available for many years in Romania, which deprives patients with mental disorders of a formidable first-line pharmacotherapeutic tool that is widely used in Europe and around the world. In the light of decades of global experience and the recommendations of the great psychiatric therapeutic guidelines, we consider it necessary to be reevaluated by our authorities, to consider the need for internal availability and the fastest possible reintroduction of lithium in Romanian practice, with net benefits, solidly proven, as well as with unparalleled efficiency in its clinical indications.   

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  13. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010;11:81–109.

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