Lithium therapy

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In lithium therapy , lithium in the form of some of its salts is used in bipolar disorder , mania or depression on the one hand as a phase prophylactic , on the other hand also to increase the effectiveness in connection with antidepressants . Another application is preventive treatment for cluster headache .

General

Lithium salts have been used as a drug in psychiatry since the middle of the 20th century and have therefore been very well researched in terms of application (side effects, tolerability, interactions).

In affective disorders such as bipolar illness or depression, lithium therapy is the only drug treatment for which a suicide-preventing effect has been clearly proven.

Lithium salts are not physically dependent and are sufficiently tolerated according to the indications given the correct dosage (see also section Side Effects ). To find the right dose it is necessary to regularly check the lithium concentration in the blood. The therapeutic range of lithium is narrow, i.e. a toxic amount is only slightly greater than that at which the desired effect occurs, which is why self-treatment can be very dangerous.

history

Since lithium urate (lithium salt of uric acid) is easily soluble in water, it was used against gout. Under the (false) uric acid diathesis of "periodic depression", the Danish psychiatrist Fritz Lange first treated depressed patients with lithium salts at the end of the 19th century. Toxic effects such as polyuria or tremor were already observed at that time. In the 1940s, the salty-tasting lithium chloride was used as a table salt substitute in the USA, resulting in severe and fatal poisoning. This prevented later use as a psychotropic drug. The anti- manic effect of lithium salts was discovered by the Australian psychiatrist John F. Cade , who first described psychopharmacological properties for lithium in 1949. From today's perspective, however, the discovery of the effect was based on a false assumption: Cade had observed that the urine of manic patients was particularly toxic when injected into guinea pigs. Under the hypothesis that urea compounds, together with other metabolic end products, trigger mental disorders and cause the effects in the animals, he administered lithium salts to the animals, assuming that the toxic lithium-uric acid compounds can be excreted via the kidneys. A psychiatric manual states:

“While conducting an experiment (with guinea pigs), Cade had discovered, rather by accident, that lithium made the animals lethargic, and he administered the drug to some of his agitated patients. [... It is also said that this was a] central moment in the history of psychopharmacology [...] "

- Kaplan & Sadock

From 1967 the Danish biochemist and psychiatrist Mogens Schou promoted lithium as phase prophylaxis for affective psychoses. John F. Cade played a key role in the further development of lithium therapy until his death. The first studies against placebo were also the first randomized, double-blind trial in psychiatry

Lithium citrate was an ingredient in the soft drink 7 Up until 1950 , before it was replaced by sodium citrate and later by potassium citrate .

Pharmaceutical information

A large number of different lithium salts can be used medicinally, for example lithium carbonate , lithium acetate , lithium sulfate , lithium citrate , lithium orotate and lithium gluconate .

pharmacology

Indications

There are three indications for lithium:

  1. Recurring episodes of depression ( unipolar recurrent depression ) or depression and mania ( manic-depressive or bipolar affective disorder ): In these patients, regular lithium intake can prevent recurrence of episodes of illness. This preventive treatment (mood stabilization) is now the main field of application for lithium salts in medicine. To treat depression, lithium salts can be added to an antidepressant if the antidepressant alone does not have a sufficient effect against the depression (so-called lithium augmentation , from the Latin augmentare "to strengthen"): A mania can also be acutely relieved by lithium administration .
  2. Therapy-resistant schizophrenia
    This is the second indication that is still in use. It is used in combination with neuroleptics.
  3. Second choice prophylactic treatment for cluster headache

Mechanism of action

How lithium works is largely unknown, as it affects countless processes in the human body. It is assumed that lithium reduces the likelihood of another affective episode by lowering an excess of noradrenaline in manic episodes and activating serotonin production in depressive episodes .

Contraindications

Absolute contraindications are

Relative contraindications are Addison's disease and - according to a more recent assessment - pregnancy (see lithium therapy and pregnancy ).

Pharmacokinetics, metabolism

The therapeutically lithium salts used dissociate after oral administration at different speeds. The lithium ions (Li + ) are well absorbed ; their permeation capacity corresponds to that of sodium ions. Compared to Na + ions have the Li + , however, ions have a lower affinity to the ion pumps and can poor running from the cells out transported are. They therefore accumulate intracellularly , which presumably contributes to the narrow therapeutic range of lithium.

Over 95% of the lithium ions in a dose are excreted in the urine . The excretion rate depends directly on the sodium concentration in the urine , since lithium and sodium compete for tubular reabsorption. A lot of sodium in the urine (e.g. high-salt diet, hypernatremia) leads to a reduced reabsorption of lithium, i.e. increased excretion. Conversely, the elimination of sodium reabsorption (e.g. by loop diuretics) increases lithium reabsorption and thus the effective concentration in the body.

The plasma half-life averages 24 hours. It is influenced by the Na + supply and generally by the kidney function .

During pregnancy , the renal excretion of lithium increases by 50–100%. Since it behaves chemically in the human organism in a similar way to Na + , which is found in all cells and body fluids , lithium crosses the placenta well and reaches approximately the same concentration in the fetus as in the maternal serum .

Chances of success

In a meta-analysis at the LMU Munich in 2004, a number of influencing factors on the effectiveness of lithium prophylaxis in bipolar affective disorders were examined. 21 effective factors were identified. The lithium response scale (LRS) was developed from this as a prognostic tool. The following factors proved to be protective, i.e. H. if present, the prognosis for the effectiveness of lithium therapy or the risk, i.e. H. if present, the prognosis is worse:

Area Protective factors (+) Risk factors (-)
Course of disease Progress pattern MDI (mania-depression-intermission), isolated episodes of illness Progression pattern DMI (Depression-Mania-Intermission), progression pattern CC (cyclical), high phase frequency, short length of the first free interval
Age Old age at first illness
Status and environment High social class and social support from the environment Unemployment, stress
therapy Compliance Long duration of illness at the start of therapy
personality Dominance High neuroticism
Comorbidity "High expressed emotions", personality disorder

Lithium Therapy and Pregnancy

After reports of malformations in newborns after the mother had been treated with lithium, lithium salts were considered dangerous teratogens from around 1970 onwards . Specifically, the non-lithium treated in children mothers very rare Ebstein's anomaly and other congenital heart defects occurred especially after Li + - exposure in early pregnancy heaped upon and led to the recommendation to administer during pregnancy not to lithium. In Denmark, a special “lithium baby register” was set up in 1968 to determine the risk.

According to more recent surveys, however, the teratogenic effects of lithium are likely to have been overestimated at the time, as the studies at the time showed considerable methodological deficiencies. There were no control groups, and the malformation rate in the rest of the population was assumed to be too low. In addition, the retrospective design presumably led to an overrepresentation of malformations. The relative risk of malformations under lithium therapy was previously given as a factor of 5–10. However, since acute manic phases or suicidality in depression can be life-threatening for the unborn child, the following recommendations now apply to lithium therapy during pregnancy:

  • If lithium therapy is absolutely necessary, consistently low serum concentrations of Li + should be aimed for - especially in the 1st  trimester ;
    • the daily dose should be divided into several individual doses,
    • a low-salt diet should be avoided.
  • In the week before the birth, the dose should - if possible - be reduced by 30–50%, since kidney clearance decreases during childbirth and, due to the narrow therapeutic range, symptoms of poisoning can occur in both the child and the mother.
  • Immediately after the delivery, the original therapy regimen that existed before the pregnancy should be resumed.
  • After Li + exposure in the 1st trimester , detailed ultrasound diagnostics or echocardiography of the fetus is recommended.

During the first two days of life, the newborn should be closely monitored, particularly for toxic symptoms .

These assessments were confirmed in a large American retrospective register-based cohort study in 2017 . In over 1.3 million children born between 2000 and 2010, 15,251 heart malformations (1.15%) were found, as well as in 16 children out of 663 who were exposed to lithium in the first trimester of pregnancy (2.41%). This resulted in the adjusted relative risk RR = 1.65. This was clearly dose-dependent with RR = 1.11 for doses of no more than 600 mg per day, RR = 1.60 for lithium intake of more than 600 mg to a maximum of 900 mg per day and RR = 3.22 for intake of more than 900 mg per day . Of the heart defects, malformations at the exit of the right ventricle, to which the Ebstein anomaly also belongs, were significantly more common with 0.60% (against 0.18% in the normal population) and an RR = 2.66. From the data it was estimated that two more children per hundred children born with a heart defect are born with lithium therapy. However, it is estimated that women receiving lithium therapy in the United States have a 5-10% higher abortion rate. Other malformations that do not affect the heart were not found significantly more frequently in the adjusted analysis.

Side effects

Typical side effects are weight gain, circulatory disorders, tremors ( tremor , especially in the hands), nausea, vomiting, changes in the blood count ( leukocytosis ), tiredness, increased thirst and increased urination, diarrhea and an underactive thyroid . The therapeutic serum level is between 0.5 and 1.0 mmol / l, depending on the indication , from 1.5 mmol / l it can lead to drowsiness, and in higher doses to cramps and coma . Due to the small therapeutic index of lithium, regular monitoring of serum levels is recommended in order to avoid undesirable drug effects. Even with the correct dosage, water and sodium losses ( diabetes insipidus ), hyperacidity of the blood ( acidosis ) and lithium nephropathy with impaired kidney function can occur during long-term treatment with lithium .

Interactions

The Li + plasma level and thus the lithium effect are influenced by all substances that have an effect on Na + excretion (see pharmacokinetics ); these primarily include diuretics with an Na + effect ( saluretics ). NSAIDs such as diclofenac or ibuprofen , and ACE inhibitors reduce also the Li + - clearance . Acetylsalicylic acid (ASA) can increase the toxicity of lithium.

The “drug course book” lists over 80 different drugs and drug groups (including luxury foods) that can interact with lithium.

Withdrawal symptoms

Slow tapering out of therapy is recommended.

Withdrawal too quickly can lead to irritability, anxiety, unstable mood and inner restlessness. In bipolar illness, the abrupt withdrawal of lithium can lead to the onset of a manic phase.

research

In 2011, scientists from the Medical University of Vienna were able to prove - similar to the results of a study from Texas in 1990 (with concentrations of up to 0.17 mg / l) and a Japanese study from 2009 - that naturally occurring lithium in drinking water has a negative effect on the regional suicide rate correlated. However, the Austrian authors distanced themselves from the idea proposed in the Texan study of artificially adding lithium to drinking water, since there is insufficient knowledge about the mechanism of action and the side effects of such a measure. “The dosage in therapy is around 100 times higher than the natural occurrence in drinking water. It is therefore still completely unclear how natural lithium develops such a strong physiological effect in drinking water. "

In this study it was found: In some regions the lithium concentration in drinking water can reach up to 5.2 mg / l, which corresponds to a daily intake of about 10 mg. A study in a small group of former drug users showed beneficial effects on mood even at a dose of 0.4 mg daily. The average or median value in Austrian drinking water, based on more than 6000 individual measurements, is around 0.01-0.03 mg / l. The highest individual value in the Graz area was 1.3 mg / l, the highest district value in Mistelbach 0.08 mg / l. The Preblauer healing water "Sunshine" from a deep borehole in Carinthia has a lithium content of 1.4 mg / l.

In addition to other side effects, lithium can inhibit thyroid function. This can lead to a goiter .

Lithium could also become important in the treatment of Alzheimer's disease or dementia , says the MedUni Vienna 2013: The element seems to be stored in the brain substance, namely more in the white than in the gray brain substance. Conversely, people who receive lithium therapy are known to produce more gray matter. "Alzheimer's disease is associated, among other things, with the breakdown and changes in white matter that lithium could counteract."

In 2016, the same research group determined the effects of lithium prescriptions on the occurrence of the light metal in drinking water with the result that the lithium content in drinking water is hardly influenced by drug residues (of the treated patients that may end up in the groundwater). In the 2013 study, this was still considered possible. In Austria, the Alpine region has particularly low values, such as in Tyrol. The value rises in lowlands where the water collects and lithium can be better removed from the rock. Comparatively high values ​​can be found in Mistelbach, in the Vienna area, in Graz and Linz, for example. In Vienna, 0.012 mg lithium has been measured in one liter of water. That is a little more than the Austrian average. The highest suicide rates are recorded in Styria, Carinthia and Salzburg. They are lowest in Burgenland, Vienna and Vorarlberg.

Trade names

Hypnorex (D), Litarex (CH), Lithiofor (CH, D), Neurolepsin (A), Priadel (CH), Quilonum, Quilonum retard (D), Quilonorm (A, CH, D)

music

In 1991 the American grunge band Nirvana released the song Lithium on their album Nevermind .

The musician Sting , who in an interview with Live! described as manic-depressive, describes the effects of lithium therapy in the song Lithium Sunset from the album: Mercury Falling .

The group Evanescence released a song called Lithium (not a cover version of the title of Nirvana) on the album The Open Door in 2006 , in which the usage is used as a metaphor for numbness and uptightness.

literature

  • Bruno Müller-Oerlinghausen , Waldemar Greil, Anne Berghöfer (eds.): Lithium therapy: benefits, risks, alternatives , 2nd edition. Springer, Berlin 1997, ISBN 3-540-62961-0 . (First published in 1986, is considered a standard German work on the subject.)
  • Mogens Schou : Lithium Therapy for Affective Disorders. Practical information for doctors, patients and relatives , 6th revised edition. Thieme, Stuttgart 2005, ISBN 978-3-13-593306-1 . (First published in 1980 under the title Lithium treatment of manic-depressive illness .)

Web links

Individual evidence

  1. ^ Suicide Prevention Strategies - A Systematic Review . In: JAMA , 2005, 294, pp. 2064-2074. PMID 16249421
  2. ^ A. .. Cipriani, K. .. Hawton, S. .. Stockton, JR Geddes: Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. In: BMJ. 346, 2013, pp. F3646 – f3646, doi: 10.1136 / bmj.f3646 .
  3. ^ Garry Walter: John Cade and Lithium. Psychiatric Services 1999; 50: 969. PMID 10402625
  4. ↑ Harold I. Kaplan, Benjamin J. Sadock: Clinical Psychiatry . Williams & Wilkins, 1988, p. 342
  5. ↑ John F. Cade: Lithium - when, why and how? In: Med J Aust. , 1975.1, pp. 684-686. PMID 1152735
  6. ↑ Lithium today - an update of its effectiveness and risks. Prof. B. Müller-Oerlinghausen; NeuroTransmitter 2019; 30 (10), pp 47-53
  7. ↑ Guideline cluster headache and trigemino-autonomic headache of the German Society for Neurology . In: AWMF online (as of 05/2015)
  8. ↑ Nikolaus Kleindienst: To predict the success of lithium prophylaxis in bipolar affective disorders . Ludwig Maximilians University, Munich 2004, urn : nbn: de: bvb: 19-23206 .
  9. ^ Schaefer, Spielmann: Medicinal prescription in pregnancy and lactation . 6th edition. Munich 2001, p. 341 f.
  10. ↑ Elisabetta Patorno, Krista F. Huybrechts, Brian T. Bateman, Jacqueline M. Cohen, Rishi J. Desai, Helen Mogun, Lee S. Cohen, Sonia Hernandez-Diaz: Lithium Use in Pregnancy and the Risk of Cardiac Malformations . In: New England Journal of Medicine , Issue 376, June 8, 2017, pp. 2245-2254; doi: 10.1056 / NEJMoa1612222
  11. ↑ laborarztpraxis-van-de-loo.de accessed on January 22, 2010
  12. ^ Jean-Pierre Grünfeld, Bernard C. Rossier: Lithium nephrotoxicity revisited . In: Nature Reviews Nephrology . 5, No. 5, May 2009, ISSN  1759-507X , pp. 270-276. doi : 10.1038 / nrneph.2009.43 . PMID 19384328 . Retrieved September 26, 2010.
  13. ↑ Pharmaceutical Course Book 2007/08. AVI Arzneimittel-Verlags-GmbH, Berlin 2007, p. 1914
  14. ^ Pharmaceutical course book 2007/08, AVI Arzneimittel-Verlags-GmbH, Berlin 2007, pp. 1914-1916.
  15. ↑ GN Schrauzer, KP Shrestha: Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. In: Biological trace element research. Volume 25, Number 2, May 1990, pp. 105-113, PMID 1699579 .
  16. ^ Message from the Medical University of Vienna dated June 1, 2011
  17. ^ Lithium in drinking water and suicide mortality by Nestor D. Kapusta et al. a., abstract from The British Journal of Psychiatry , April 2011
  18. ↑ V.Faust, lithium salts
  19. ↑ meduniwien.ac.at
  20. ↑ bmgf.gv.at (PDF)
  21. ↑ meduniwien.ac.at
  22. ↑ ABDA database (as of September 1, 2008) of DIMDI
  23. ↑ Austria Codex (as of September 1, 2008)
  24. ↑ You don't have to be bipolar to be a genius - but it helps . In: The Independent . February 3, 2010 ( independent.co.uk [accessed August 5, 2017]).