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LITHIUM THERAPY PRESENTATION final draft.pptx
The document outlines lithium therapy, detailing its historical development, pharmacology, indications, and management guidelines. It emphasizes lithium's effectiveness in treating acute mania, mood disorders, and other psychological conditions, while discussing necessary monitoring for side effects and potential toxicities. Additionally, it addresses contraindications and special considerations for specific populations, concluding with its status as a first-line treatment for bipolar disorder in certain regions.
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LITHIUM THERAPY PRESENTATION final draft.pptx
- 1. LITHIUM THERAPY IGBINLADE ADEDAMOLASEGUN. (M.D.) V.N KARAZIN NATIONAL UNIVERSITY, KHARKOV, UKRAINE. JUNIOR RESIDENT DOCTOR, FEDERAL TEACHING HOSPITAL IDO-EKITI, EKITI STATE, NIGERIA.
- 2. OUTLINE • INTRODUCTION • HISTORY •INDICATION • PHARMACOLOGY • ADVERSE EFFECTS • CONTRAINDICATIONS • POSSIBLE COMBINATIONS • SPECIAL GROUPS • CONCLUSION
- 3. INTRODUCTION • Lithium (Li),a monovalent ion, is a member of the group 1A alkali metals on the periodic table, a group that also includes sodium, potassium, rubidium, cesium, and francium. Lithium exists in nature as both 6Li (7 .42%) and 7Li (92.58% ). The latter isotope allows the imaging of lithium by magnetic resonance spectroscopy. • Lithium is a mood stabilizing drug
- 4.
- 5. HISTORY Landmarks in thehistory of lithium • 1817 Johan August Arfvedson discovers lithium • 1843 Alexander Ure introduces lithium in modern medicine • 1855 William Thomas Brande fully isolates lithium • 1870s William Hammond - anecdotal evidence of lithium bromide in treatment of acute mania • 1890s Carl Lange - systematic use of lithium in the acute and prophylactic treatment of depression
- 6. History • 1900s Toxicityreports – weakness, tremor, diarrhea, vomiting and deaths • 1932 Lithium disappears from British Pharmacopoeia • 1940s Use as sodium substitute in low-sodium diets • 1949 Removal from American markets following reports of severe intoxication • 1949 John F. J. Cade - use of lithium in acute mania • 1950 to 1974 Intense clinical research into safety and efficacy of lithium • 1968 American Journal of Psychiatry recognizes the clinical significance of lithium • 1970 USFDA approval for treatment of mania • 1974 USFDA approval for maintenance therapy of patients with mania
- 7. INDICATION Lithium Placebo- controlledtrials have shown that lithium is effective in a number of conditions, including the following: • The acute treatment of mania • The prophylaxis of unipolar and bipolar mood disorder • Augmentation therapy in resistant depression • The prevention of aggressive behaviour in patients with learning disabilities. Aggressive outbursts in persons with schizophrenia, violent prison inmates, and children with conduct disorder and aggression, or self-mutilation in persons with mental retardation can sometimes be controlled with lithium • Severe cyclothymic disorder
- 8. PHARMACOLOGY • Absorption: Itis rapidly and completely absorbed after oral administration, with peak serum concentrations occurring in 1 to 1.5 hours with standard preparations and in 4 to 4.5 hours with slow-release and controlled-release preparations. • Distribution: Lithium does not bind to plasma proteins, distributed in the body, mainly intracellularly to the liver and kidneys. • Metabolism: It is not metabolized. • Excretion: It is excreted through the kidneys.
- 9. Pharmacology • The plasmahalf-life is initially 1.3 days, and it becomes 2.4 days after administration for more than 1 year. • The elimination half-life of lithium is 18 to 24 hours in young adults, but it is shorter in children and longer in elderly persons. Renal clearance of lithium is decreased with renal insufficiency. Equilibrium is reached after 5 to 7 days of regular intake.
- 10. Mechanism of action •An explanation for the mood-stabilizing effects of lithium remains elusive. Theories include alterations of ion transport and effects on neurotransmitters and neuropeptides, signal transduction pathways, and second messenger systems. • A.) Glycogen synthase kinase 3 (GSK3), cAMP response element-binding protein (CREB) and Na(+)/K(+) ATPase-related mechanisms may be important for lithium’s effects. At clinically relevant doses, lithium inhibits the formation of cyclic adenosine monophosphate (cAMP) and also attenuates the formation of various inositol lipid- derived mediators. • B.) Lithium may have neuroprotective effects that preserve the function of neurones and neuronal circuits. • C.) Lithium also promotes the creation of new neurones (neurogenesis) in the hippocampus, which is potentially important for learning, memory and stress responses
- 11. Mechanism of action •D.) Although the older literature pertaining to the possible neuroprotective effect of lithium consisted largely on either in vitro or animal studies, a meta-analysis suggests that lithium may prevent transition to dementia. • E.) Uncertain numerous effects on biological systems (particularly at high concentrations). Lithium can substitute for Na2+, K+, Ca2+, Mg2+ and may have effects on cell membrane electrophysiology. Within cells, lithium interacts with systems involving other cations, including the release of neurotransmitters and 2nd messenger systems, (e.g. adenylate cyclase, inositol 1,4,5,-triphosphate, arachidonate, protein kinase C, G proteins and calcium), effectively blocking the actions of transmitters and hormones.
- 12. Mechanism of action •F.) lithium also affects the circadian system, resulting in a lengthening of circadian period. • G.) More recent interest has focused on the ability of lithium to promote cell survival and increase synaptic plasticity, perhaps through inhibition of the activity of the enzyme glycogen synthase kinase- 3 (GSK- 3).
- 13. Dosage and plasmaconcentrations • Lithium has a narrow therapeutic index. 0.8-1.2mmol/l • Because the therapeutic and toxic doses are close together, it is essential to measure plasma concentrations of lithium during treatment. Measurements should first be made after about 7 days, then about every 2 weeks, and then, provided that a satisfactory steady state has been achieved, once every 6 weeks. Subsequently, lithium levels are often very stable, and serum measures can be carried out at intervals of approximately 3 months unless there are clinical indications for more frequent monitoring.
- 14. Dosaging • After anoral dose, serum lithium levels rise by a factor of two or three within about 4 hours. For this reason, concentrations are normally measured approximately 12 hours after the last dose, usually that given at night. It is important to follow this routine, as published information about lithium levels refers to the concentration 12 hours after the last dose, and not to the ‘peak’reached in the 4 hours after that dose.If an unexpectedly high concentration is found, it is important to establish whether the patient has inadvertently taken a morning dose before the blood sample was taken. • Previously, the accepted range for prophylaxis was 0.7– 1.2 mmol/ l measured 12 hours after the last dose. However, current trends are to maintain lithium at lower serum levels because this decreases the burden of side effects
- 15. Dosaging • In thetreatment of acute mania, serum concentrations below 0.8 mmol/l appear to be ineffective, and a range of 0.8– 1.0 mmol/ l is probably required. Serious toxic effects appear with concentrations above 2.0 mmol/ l, although early symptoms may appear at concentrations above 1.2 mmol/ l. • Liquid formulations of lithium citrate are available for patients who have difficulty in taking tablets(lithium carbonate). • Lithium may be administered once- or twice- daily. Frequency of administration does not appear to affect urine volume. In general, it is more convenient to take lithium as a single dose at night, but patients who experience gastric irritation on this regimen may be helped by divided daily doses
- 16. . • Each ofthe lithium carbonate 400mg tablets contains 10.8mmol/l. • Lithium citrate liquid is available in two strengths and should be administered twice daily: • ■■ 5.4mmol/5mL is equivalent to 200mg lithium carbonate. • ■■ 10.8mmol/5mL is equivalent to 400mg lithium carbonate.
- 17. . • . •. Lithium citrate Lithium bromide
- 18.
- 19. Guidelines on lithiumtherapy • Prior to commencing lithium therapy: physical examination, FBC, U&Es, TFTs, renal function (eGFR), baseline weight and height (BMI), if clinically indicated—ECG, pregnancy test. • Starting dose: usually 400–600mg given at night, increased weekly depending on serum monitoring to max 2g (usual dose 800mg–1.2g) — actual dose depends upon preparation used (molar availability varies even when amounts (mg) are the same.
- 20. . • Monitoring: checklithium level 7 days after starting and 7 days after each change of dose. Take blood samples 12hr post-dose. Once a therapeutic serum level has been established: continue to check lithium level/eGFR every 3mths, TFTs every 6mths, monitor weight (BMI), and check for side-effects. • Stopping: reduce gradually over 1–3mths, particularly if patient has history of manic relapse (even if started on other anti-manic agent).
- 21. Drug interactions . Increased lithiumlevels ● Diuretics (furosemide is safest) ● Non- steroidal anti- inflammatory drugs (aspirin/ sulindac is safest) ● ACE inhibitors ● Angiotensin- II- receptor antagonists ● Antibiotics (metronidazole) Decreased lithium levels ● Theophylline ● Sodium bicarbonate Effects ● 5- HT neurotoxicity SSRIs (can be used safely with care) ● Extrapyramidal side effects enhanced Antipsychotic agents, metoclopramide, domperidone ● Enhanced neurotoxicity Carbamazepine, phenytoin, calcium- channel blockers,
- 22. Safer lithium therapy •The following recommendations were made: • Patients should be monitored in accordance with NICE guidelines. • There are reliable systems to ensure blood test results are communicated between laboratories and prescribers. • Throughout their treatment patients receive appropriate ongoing verbal and written information and complete a record book.*
- 23. Safer lithium therapy •Prescribers and pharmacists check that blood tests are monitored regularly and that it is safe to prescribe and/or dispense lithium. • Systems are in place to identify and deal with medicines that might adversely interact with lithium therapy.
- 24. Side Effects • Upto 80 percent of people on lithium will experience a form of side effect. Severity: • Mild to moderate intoxication (lithium level of 1.5-2.0 mEq/L) GI Vomiting, Abdominal pain, Dryness of mouth, Neurological Ataxia, Dizziness, Slurred speech, Nystagmus, Lethargy or excitement Muscle weakness
- 25. . • Moderate tosevere intoxication (lithium level: 2.0-2.5 mEq/L) GI Anorexia, Persistent nausea and vomiting, Neurological Blurred vision, Muscle fasciculations, Clonic limb movements, Hyperactive deep tendon reflexes, Choreoathetoid movements, Convulsions, Delirium, Syncope, Electroencephalographic changes, Stupor, Coma, Circulatory failure (lowered BP, cardiac arrhythmias, and conduction abnormalities) • Severe lithium intoxication (lithium level >2 .5 mEq/L) Generalized convulsions, Oliguria and renal failure, Death.
- 26. Adverse Effect • Bybody system: • Neurological • Cardiovascular • Gastrointestinal • Endocrine • Urogenital/Renal • Hematology • Dermatology
- 27. Management of LithiumToxicity • Management of Lithium Toxicity • 1 . Contact personal physician or go to a hospital emergency department. • 2 . Lithium should be discontinued • 3 . Vital signs and a neurological examination with complete formal mental status examination. • 4. Lithium level, serum electrolytes, renal function tests, and ECG • 5. Emesis, gastric lavage, and absorption with activated charcoal. • 6. For any patient with a serum lithium level greater than 4.0 mEq/L, hemodialysis
- 28. Contraindications Contraindications • These includerenal failure or recent renal disease, • Current cardiac failure or recent myocardial infarction, and • Chronic diarrhoea sufficient to alter electrolytes. • Lithium should not be prescribed if the patient is judged to be unlikely to observe the precautions required for its safe use. This includes a propensity to discontinue it suddenly against advice.
- 29. Is lithium stillworth it? • In the UK, lithium is still regarded as the first choice of mood stabilizer, although in the USA valproate is the most popular choice because of its better tolerability. However, the evidence for its long- term prophylactic efficacy is less complete. In addition, there is evidence that the supervised use of lithium is associated with a decreased risk of suicidal behaviour in bipolar illness.
- 30. Special groups • Lithiumin child and adolescent: MR and CD • Elderly • Pregnant Women • Youth • PLWHA
- 31. Guidelines for specialgroups For all women of child-bearing age: • Always consider (and ask about) the possibility of pregnancy. • Pregnancy test recommended before starting any teratogenic drug. • Counsel the patient about the necessity of adequate contraception. • Advise further consultation if pregnancy is planned. For a planned conception: • Discuss risks/benefi ts of discontinuation/continuation of medication (e.g. relapse vs. teratogenicity, possible time it may take to conceive, no decision is risk-free). • Avoidance of all drugs during the first trimester (max teratogenic potential is between wks 2–9) is ideal, but often not achievable.
- 32. . In pregnancy: • Considerswitching to a lower risk drug if possible, use the lowest viable dose, avoid polypharmacy, and monitor closely. • Pregnancy may alter the pharmacokinetics of drugs, hence dosages may need to be adjusted (e.g. lithium). • Gradual withdrawal of some compounds (e.g. BDZs, TCAs, SSRIs) in the weeks prior to delivery may help avoid ‘withdrawal’ effects in the newborn baby. • Lithium is a category D drug according to the FDA in pregnancy, I.e. Human fetal risk seen (may be used in life-threatening situation)
- 33. . Unexpected pregnancy: • Ifafter week nine, no urgent decision needs to be made as major risk has passed. • Consider reducing dose if possible and prescribe nutritional supplements (e.g. folic acid). • Do not stop lithium abruptly and use caution with some SSRIs and anticonvulsants.
- 34. Withdrawal effects fromlithium • Physical. Psychological • ■■ Tremor • ■■ Polyuria • ■■ Muscular weakness • ■■ Polydipsia • ■■ Dryness of mouth ■■ Anxiety ■■ Nervousness ■■ Irritability ■■ Alertness ■■ Sleep disturbances ■■ Elated mood/mania ■■ Depressed mood
- 35.
- 36. Conclusion • Lithium therapyin psychiatry seems to have found its footing. • Should it still be looked upon as the 1st line for bipolar 1 looking at its slow onset of action
- 37. References • Shorter Oxfordtextbook of Psychiatry 7th edition. • Kaplan textbook of Psychiatry. • Oxford handbook of Psychiatry 3rd edition • Maudsleys textbook of prescriptions 14th edition
- 38.
Editor's Notes
- #3 Finally, in the near future, neuroimaging of lithium may assist the clinician through the identification of biomarkers of response to lithium and through the direct measurement of lithium brain concentrations using MRI spectroscopy It never occurs freely in nature, but only in (usually ionic) compounds, such as pegmatitic minerals, which were once the main source of lithium. Due to its solubility as an ion, it is present in ocean water and is commonly obtained from brines
- #5 Lithium was first discovered and defined by Johan August Arfvedson in 1817 when he did an analysis of the mineral petalite [LiAl(Si2O5)2]. Petalite was first found by Brazilian scientist Josá Bonifécio Andrade e Silva in 1800. Lepidolite, spodumene, petalite and amblygonite are the more important minerals containing lithium. It was Arfvedson's laboratory chief John Jacob Berzelius who named this alkali metal “lithion.” Arfvedson was never able to fully isolate lithium, and it wasn't until 1855 that it was isolated by William Thomas Brande. Brande and Sir Humphrey Davy earlier had done electrolysis on lithium oxide in 1818. Lithium was first produced commercially in 1923 by Metallgesellschaft AG. The use of lithium for medicinal purposes can be traced back 1,800 years to the Greek physician Galen, who treated patients with mania by having them bathe in alkaline springs and drink the water, which probably contained lithium. In 1843 Alexander Ure introduced lithium into modern medicine, and he showed the in vitro reduction of weight of a uric acid bladder stone in a lithium carbonate solution. Sir Alfred Garrod later discovered that gouty uric acid deposits also were soluble in lithium solution. The view in that time was that uric acid imbalances caused a wide range of diseases, and Armand Trousseau and Alexander Haig proposed that mania and depression also may result from this imbalance and lithium may be effective in these conditions. In the 1840s, lithium was mixed with carbonate or citrate to form a salt and was used to treat gout, epilepsy, diabetes, cancer and insomnia. In the 1870s, the then American Surgeon General William Hammond had provided anecdotal evidence for the use of lithium bromide in the treatment of acute mania. In the 1880s and 1890s the Lange brothers Carl and Fritz used lithium in depression, and Carl Lange was the first to systematically use lithium in the acute and prophylactic treatment of depression.The introduction of lithium preparations and tablets in the 1900s brought to the fore the toxic effects of the drug; and there were reports of weakness, tremor, diarrhea, vomiting and deaths. The drug disappeared from the British Pharmacopoeia by 1932, but later in the 1940s it was used as a sodium substitute in low sodium diets; but the reports of severe intoxication led to its removal from American markets in 1949. The appearance in 1949 in the Medical Journal of Australia of a paper entitled “Lithium salts in the treatment of psychotic excitement” by John F. J. Cade was an unspectacular entry into a new era of psychiatry. Manic patients showed improvement, with the patient becoming calmer after four to five days. There was no improvement in the excited schizophrenic patients, though there was a calming effect. There was no improvement or deepening of depression. The action of lithium in reducing mania was a chance finding by Cade (1949), who had been investigating the effects of urates in animals and had decided to use the lithium salt because of its solubility. Lithium is a toxic agent, so Cade’s important observations did not have a significant impact on clinical practice until the following decade, when controlled trials showed that lithium was effective in both the acute treatment of mania and the prophylaxis of recurrent mood disorders. The paper also gave details of initial dosage, maintenance doses, appearance of toxic symptoms and warning about lithium over-dosage. Most of the subsequent evidence on lithium was gathered by the European trials, especially by Mogens Abelin Schou from Denmark. The earliest report of lithium treatment in North America was published in 1960. Between 1950 and 1974, 782 papers were published on lithium from Europe, 353 papers from North America and 95 papers from other continents; and this led to the establishment of lithium as an efficacious and well-tolerated drug in mania. The clinical significance of lithium was recognized in a special section of the American Journal of Psychiatry in 1968. In 1970 it was approved by the United States Food and Drug Administration (USFDA) for the treatment of mania, and in 1974 it was approved for maintenance therapy of patients with mania.
- #7 the addition of lithium to antidepressant drug treatment is usually safe and well tolerated. About 50% of depressed patients will show a useful response over 1–3 weeks.
- #8 Pharmacokinetics Lithium is rapidly absorbed from the gut and diffuses quickly throughout the body fluids and cells. Lithium moves out of cells more slowly than sodium. It is removed from the plasma by renal excretion and by entering cells and other body compartments. Therefore there is rapid excretion of lithium from the plasma, and a slower phase reflecting its removal from the whole- body pool. The blood-brain barrier permits only slow passage of lithium, which is why a single overdose does not necessarily cause toxicity and why long-term lithium intoxication is slow to resolve. Like sodium, lithium is filtered and partly reabsorbed in the kidney. When the proximal tubule absorbs more water, lithium absorption increases. Therefore dehydration causes the plasma lithium concentration to rise. Because lithium is transported in competition with sodium, more is reabsorbed by the kidney when sodium concentrations fall. This is the mechanism whereby thiazide diuretics can lead to toxic concentrations of lithium in the blood. Lithium is filtered passively and then partly reabsorbed by the same mechanism that absorbs sodium. The two ions compete for this mechanism; hence reabsorption of lithium increases when that of sodium is reduced (e.g. by thiazide diuretics). The mechanism of action of lithium is not known. It is rapidly absorbed, has a small volume of distribution, and is excreted in the urine unchanged (there is no metabolism of lithium). The half-life of lithium is 18 to 30 hours. It has lower absorption on an empty stomach
- #9 Plasma concentrations of drugs vary throughout the day, rising immediately after the dose and falling at a rate that differs between individual drugs. The rate at which a drug level declines after a single dose ranges from hours for lithium carbonate to weeks for slow- release preparations. Knowledge of these differences allows more rational decisions. Obesity is associated with higher rates of lithium clearance. The blood-brain barrier permits only slow passage of lithium, which is why a single overdose does not necessarily cause toxicity and why long-term lithium intoxication is slow to resolve.
- #10 Lithium promotes gabaergic neurotransmission: affects both pre and postsynaptic neurons at the gaba receptors and increases the gaba level in the csf. Presynaptic facilitates gaba release. Postsynaptic upregulates gabab Lithium downregulates nmda receptors Glutamate increases in excitatory nt in mania Lithium inhibits ippase and impase: Ippase and impase= phosphoinositides. Ippase and impase helps in the synthesis of myoinositol. Depletion of this myoinositol = mania Lithium inhibits GSK-3, PKC, MARCKS Glycogen synthase kinase 3 responsible for gene transcription, synaptic activity, activated under conditions of chronic stress. Lithium attenuates influx of calcium after nmda receptor activation. Lithium reduces excitoxicity via modulation of calcium entry
- #13 Therapeutic index: relative measure of toxicity or safety of drug; ratio of median toxic dose to the median effective dose Median toxic dose: dose at which 50% of patients experience specified toxic effect; median effective dose = dose at which 50% of patients experience specified therapeutic effect
- #14 Severus et al. (2008) concluded that, in the prophylaxis of bipolar disorder, the minimum efficacious serum level of lithium was 0.4 mmol/ l, but in most patients the best therapeutic response was obtained with levels in the range 0.6– 0.75 mmol/ l. Higher levels benefited some patients with more persistent manic symptomatology.
- #16 Lithium preparations (UK) Preparation Active component Available strengths Eskalith (tablet) lithium carbonate 300mg or 150mg, Eskalith CR is 450mg. CamcolitR (tablets) Lithium carbonate 250/400mg (scored) Li-liquidR (oral solution) Lithium citrate 509mg/5mL LiskonumR (tablets) Lithium carbonate 450mg (scored) PriadelR (tablets) Lithium carbonate 200/400mg (scored) PriadelR (liquid) Lithium citrate 520mg/5mL
- #18 Efficacy. Does the intervention work under carefully controlled (‘ideal’) conditions? ● Effectiveness. Does the intervention work when provided under the usual circumstances of health care practice? ● Efficiency. What is the effectiveness of the intervention in relation to the resources that it consumes (i.e. its cost- effectiveness or cost– benefit)? Lithium treatment is efficacious in the prophylaxis of bipolar disorder, but appears to have disappointing effectiveness mainly because under standard clinical conditions many patients do not take lithium reliably.
- #20 The management of patients on lithium Preparation. A careful routine of management is essential because of the effects of therapeutic doses of lithium on the thyroid and kidney, and the toxic effects of excessive dosage. The following routine is one of several that have been proposed, and can be adopted safely. Successful treatment requires attention to detail, so the steps are described below at some length. Before starting lithium, a physical examination should be performed, including the measurement of blood pressure. It is also useful to weigh the patient and calculate the BMI. Blood should be taken for estimation of electrolytes, calcium, creatinine, e- GFR, and a full blood count. Thyroid function tests are also necessary. If indicated, an ECG and pregnancy tests should be performed as well. If these tests show no contraindication to lithium treatment, the doctor should check that the patient is not taking any drugs that might interact with lithium. A careful explanation should then be given to the patient. They should understand the possible early toxic effects of an unduly high blood concentration, and also the circumstances in which this can arise— for example, during intercurrent gastroenteritis, renal infection, or the dehydration secondary to fever. They should be advised that if any of these arise, they should stop the drug and seek medical advice. It is usually appropriate to include another member of the family in these discussions. Providing printed guidelines on these points is often helpful (either written by the doctor, or in one of the forms provided by pharmaceutical firms). In these discussions a sensible balance must be struck between alarming the patient by overemphasizing the risks, and failing to give them the information that they need to take a collaborative part in the treatment. Starting treatment. Lithium should normally be prescribed as the carbonate, and treatment should begin and continue with a single daily dose unless there is gastric intolerance, in which case divided doses can be given. If the drug is being used for prophylaxis, it is appropriate to begin with 200– 400 mg daily in a single dose. The lower end of the range is appropriate when patients are taking concomitant medication such as SSRIs that might interact with lithium. (There are 2 different types of lithium – lithium carbonate and lithium citrate. It's important not to change to a different type unless your doctor has recommended it. This is because different types are absorbed differently in the body. Lithium carbonate comes as regular tablets and slow-release tablets – where the medicine is released slowly over time. Lithium citrate comes as a liquid. This is usually only prescribed for people who have trouble swallowing tablets . Doses vary from person to person. Your starting dose will depend on your age, what you're being treated for and the type of lithium your doctor recommends. If you have kidney problems your doctor will monitor the level of lithium in your blood even more closely and change your dose if necessary. You will usually take your lithium once a day, at night. This is because when you have your regular blood test, you need to have it 12 hours after taking your medicine. You can choose when you take your lithium – just try to keep to the same time every day.) Blood should be taken for lithium estimations every week or two, adjusting the dose until an appropriate concentration is achieved. A lithium level of 0.4– 0.7 mmol/l (in a sample taken 12 hours after the last dose) may be adequate for prophylaxis, as explained above. If this is not effective, the previously accepted higher range of 0.8– 0.9 mmol/ l can be tried if side effects permit and the predominant symptomatology is manic. When judging the response, it should be remembered that several months may elapse before lithium achieves its full effect. Continuation treatment. As treatment continues, lithium estimations should be carried out about every 12 weeks. It is important to have some means of reminding patients and doctors about the times at which repeat investigations are required. Computerized databases may be helpful in this respect. Every 6 months, blood samples should be taken for electrolytes, urea, creatinine, e- GFR, calcium, and thyroid function tests. If two consecutive thyroid function tests 1 month apart show evidence of hypothyroidism, lithium should be stopped or L- thyroxine prescribed. Troublesome polyuria is a reason for attempting a reduction in dose, whereas severe persistent polyuria is an indication for specialist renal investigation, including tests of concentrating ability. A persistent leucocytosis is not uncommon and is apparently harmless. It reverses soon after the drug is stopped. When lithium is given, the doctor must keep in mind the interactions that have been reported with psychotropic and other drugs (see above). It is also prudent to be extra vigilant for toxic effects if ECT is being given. If the patient requires an anaesthetic for any reason, the anaesthetist should be told that they are taking lithium; this is because, as noted above, there is some evidence that the effects of muscle relaxants may be potentiated. Lithium is usually continued for at least a year, and often for much longer. The need for the drug should be reviewed once a year, taking into account any persistence of mild mood fluctuations, which suggest the possibility of relapse if treatment is stopped. Continuing medication is more likely to be needed if the patient has previously had several episodes of mood disorder within short time, or if previous episodes were so severe that even a small risk of recurrence should be avoided. Some patients have taken lithium continuously for 15 years or more, but there should always be compelling reasons for continuing treatment for more than 5 years. As noted above, lithium should be withdrawn slowly, over a number of months if possible. The patient should be advised not to discontinue lithium suddenly on their own initiative.
- #22 ECT and surgery. It is possible that the continuation of lithium during ECT may lead to neurotoxicity. If feasible, lithium treatment should be suspended or serum levels reduced during ECT, because the customary overnight fast beforehand may leave patients relatively dehydrated the following morning. If possible, lithium treatment should be discontinued before major surgery, because the effects of muscle relaxants may be potentiated. However, the risk of acute withdrawal and ‘rebound’ mania must be considered. NSAIDs and COX-2 inhibitors reduce the renal excretion of lithium via their action on renal prostaglandins, resulting in increased plasma lithium levels. ACE inhibitors enhance the tubular reabsorption of lithium, and diuretics promote renal sodium wasting. They increase the risk of hospital admission for lithium toxicity Metronidazole raises lithium levels by decreasing its renal clearance When these two medicines are taken together, theophylline and medicines related to theophylline, including caffeine, may increase the amount of lithium output in your urine Sodium bicarbonate may increase the excretion rate of Lithium hydroxide which could result in a lower serum level and potentially a reduction in efficacy.
- #23 The UK National Patient Safety Agency (NPSA) issued a Patient Safety Alert (NPSA/2009/PSA005) on safer lithium therapy. This was in response to reports of harm caused to patients, including fatalities, by lithium therapy and was developed in collaboration with the Prescribing Observatory for Mental Health (POMH-UK) of the RCPsych, the National Pharmacy Association (NPA), other organizations, clinicians, and patients. It was designed to help NHS organizations, including community pharmacies, in England and Wales (and latterly Scotland) to take steps to minimize the risks associated with lithium therapy.
- #25 lithium= Decreased thyroxine with increased TSH. Goitre,hyperparathyroidism (rare) carbamazepine= Decreased thyroxine with normal TSH
- #26 Indications for referral to a specialist renal physician in a patient taking lithium Referral is required if any of the following are present: ● e- GFR is decreasing by >4 ml/ min annually ● progressive rise in blood creatinine concentration in three or more serial tests ● proteinuria ● haematuria ● symptoms suggestive of chronic renal failure (e.g. tiredness, anaemia) ● e- GFR <30 ml/ min.
- #27 In some patients, impaired erection has been reported. A mild diuresis due to sodium excretion occurs soon after the drug is started. Other common effects include tremor of the hands, dry mouth, a metallic taste, feelings of muscular weakness, and fatigue. Some degree of mild thirst and polyuria is common in patients taking lithium, probably because lithium blocks the effect of antidiuretic hormone on the renal tubule. This may not be of clinical significance, but up to one- third of patients can show progression to a diabetes insipidus- like syndrome with pronounced polyuria and polydipsia. This may necessitate withdrawal of lithium treatment, although the use of lower serum lithium levels may cause the syndrome to remit. Some patients, especially women, gain weight when taking the drug. Persistent fine tremor, mainly affecting the hands, is common, but coarse tremor suggests that the serum concentration of lithium has reached toxic levels. Most patients adapt to the fine tremor; for those who do not, propranolol up to 40 mg three times daily may reduce the symptom. Lithium-Induced Postural Tremor The /3-receptor antagonists are beneficial for lithium-induced postural tremor and other medication-induced postural tremors-for example, those induced by tricycle antidepressants (TCAs) and valproate (Depakene ). The initial approach to this movement disorder includes lowering the dose of lithium (Eskalith), eliminating aggravating factors, such as caffeine, and administering lithium at bedtime. If these interventions are inadequate, however, propranolol in the range of 20 to 160 mg a day given two or three times daily is generally effective for the treatment of lithium-induced postural tremor. Both hair loss and coarsening of hair texture can occur. Thyroid gland enlargement occurs in about 5% of patients who are taking lithium. The thyroid shrinks again if thyroxine is given while lithium is continued, and it generally returns to normal a month or two after lithium has been stopped. Lithium interferes with thyroid production, and hypothyroidism occurs in up to 20% of women patients, with a compensatory rise in thyroid stimulating hormone. Tests of thyroid function should be performed every 6 months to help to detect these changes, but these intermittent tests are no substitute for a continuous watch for suggestive clinical signs, particularly lethargy and substantial weight gain. If hypothyroidism develops and the reasons for lithium treatment are still strong, thyroxine treatment should be added. Lithium has also been associated with elevated serum calcium levels in the context of hyperparathyroidism. This is occasionally associated with severe depression, making distinction from the underlying mood disorder difficult. Reversible ECG changes also occur. These may be due to displacement of potassium in the myocardium by lithium, as they resemble those of hypokalaemia, with T- wave flattening and inversion or widening of the QRS. They are rarely of clinical significance. Other changes include a reversible leucocytosis and occasional papular or maculopapular rashes. Effects on memory are sometimes reported by patients, who complain in particular of everyday lapses of memory, such as forgetting well- known names. It is possible that this impairment of memory is caused by the mood disorder rather than by the drug itself, but there is also evidence that lithium can be associated with impaired performance on certain cognitive tests. Long- term effects on the kidney. As noted above, lithium treatment decreases tubular concentrating ability and can occasionally cause a nephrogenic diabetes inspidus. In addition, there have been reports that over many years of treatment, lithium can sometimes cause an increasing and in some cases irreversible decline in tubular function. This may be more likely in patients with higher serum concentrations of lithium, and where concomitant psychotropic medication has been employed (Macritchie and Young, 2004). Several follow- up studies have examined the effect of longer- term lithium maintenance treatment on glomerular function. In general, it has been thought that any decline in glomerular function is usually mild and related to lithium intoxication. However, more recent epidemiological studies suggest that lithium treatment is associated with an increased risk of chronic kidney disease, particularly in patients with a greater number of prescriptions for lithium (Kessing et al., 2015). Whether lithium is associated with an increased risk of end- stage renal failure is unclear (Close et al., 2014; Kessing et al.,2015). Clarifying this possibility is difficult because patients with bipolar disorder (the group most likely to receive lithium) may have an increased risk of renal disease anyway through associated medical morbidities; for example, hypertension and diabetes (see Chapter 10). With the current trends towards long- term prophylaxisof mood disorders, it is clearly wise to monitor plasma creatinine levels regularly and to supplement this with estimated glomerular filtration rate (e- GFR; see Box 25.10). It seems likely that the risk of nephrotoxicity will be minimized by maintaining plasma lithium levels at the lower end of the therapeutic range, provided that they are therapeutically effective for the individual patient. Also, careful attention to medical comorbidity in bipolar patients is important. Toxic effects These are related to dose. They include ataxia, poor coordination of limb movements, muscle twitching, slurred speech, and confusion. They constitute a serious medical emergency, as they can progress through coma and fits to death. If these symptoms appear, lithium must be stopped at once and a high intake of fluid provided, with extra sodium chloride to stimulate an osmotic diuresis. In severe cases, renal dialysis may be needed. Lithium is rapidly cleared if renal function is normal, so that most cases either recover completely or die. However, cases of permanent neurological and renal damage despite haemodialysis have been reported. As noted earlier, lithium can increase fetal abnormalities, particularly of the heart, although the magnitude of the individual risk is low. The decision as to whether or not to continue with lithium treatment during pregnancy must therefore be carefully considered. Important factors include the likelihood of affective relapse if lithium is withheld, and the difficulty that could be experienced in managing an episode of affective illness in the particular individual.
- #30 Lithium Treatment of mania Five placebo- controlled trials have shown that lithium is effective in the acute treatment of mania (Cipriani et al., 2011). In the only study that compared lithium with both placebo and an active comparator, Bowden et al. (1994) found a response rate of 49% for lithium, 48% for valproate, and 25% for placebo. In general, lithium is as effective as an antipsychotic medication, but its onset of action is slower. Moreover, in highly active states, antipsychotic medication may be preferable (Goodwin et al., 2016). Prominent depressive symptoms and psychotic features predict a poorer response to lithium alone, as does a rapid cycling disorder.
- #31 LITHIUM IN CHILD AND ADOLESCENT CHILDREN AND ADOLESCENT There is some support for the use of lithium in childhood bipolar disorder. Risperidone, aripiprazole, and quetiapine have all been licensed by the Food and Drug Administraiton (FDA) to treat mania or mixed states in 10– 17- year- olds. LITHIUM IN CHILD AND ADOLESCENT Lithium-antiaggression properties, Studies support use in MR and CD for aggressive and selfinjurious behaviors; can be used for same in POD; also indicated for early-onset bipolar disorder. 600-2,100 mg in two or three divided doses; keep blood levels to 0.4-1 .2 mEq/L. Adverse reaction= Nausea, vomiting, polyuria, headache, tremor, weight gain, hypothyroidism Experience with adu lts suggests renal function monitoring ELDERLY Management of bipolar disorder in the elderly follows the principles described for younger patients (Goodwin et al., 2016). Lithium prophylaxis remains valuable, but blood levels should be monitored with particular care and kept at the lower end of the therapeutic range (0.4– 0.6 mmol/ l). Elderly Persons Lithium is a safe and effective drug for elderly persons. However, the treatment of elderly persons taking lithium may be complicated by the presence of other medical illnesses, decreased renal function, special diets that affect lithium clearance, and generally increased sensitivity to lithium. Elderly persons should initially be given low dosages, their dosages should be switched less frequently than those of younger persons, and a longer time must be allowed for renal excretion to equilibrate with absorption before lithium can be assumed to have reached its steadystate concentrations. PUEPERAL PSYCHOSIS As with other psychoses, antipsychotics are a mainstay of treatment, with antidepressants also used if depressive symptoms are prominent. Adjunctive benzodiazepines are helpful for insomnia and sleep disturbance. Lithium may also be worth considering if there is a clear bipolar component, though it is advised that women taking lithium should not breastfeed. Where pharmacological treatment and psychological support do not resolve symptomatology, the early use of ECT, which can be rapidly effective in puerperal psychosis, should be considered. For review, see Bergink et al. (2015). Pregnant Women Lithium should not be administered to pregnant women in the first trimester because of the risk of birth defects. The most common malformations involve the cardiovascular system, most commonly Ebstein's anomaly of the tricuspid valves. The risk of Ebstein's malformation in lithium-exposed fetuses is one in 1,000, which is 20 times the risk in the general population. The possibility of fetal cardiac anomalies can be evaluated with fetal echocardiography. The teratogenic risk of lithium (4 to 1 2 percent) is higher than that for the general population (2 to 3 percent) but appears to be lower than that associated with the use of valproate or carbamazepine. Lithium in Youth The Collaborative Lithium Trials (CoLT) established a set of protocols to establish the safety and potential efficacy of lithium in youth, and to develop studies to provide evidence-based dosing of lithium for youth. A group of researchers recently studied the first-dose pharmacokinetics of lithium carbonate in youth and found that clearance and volume are correlated with total body weight in youth, and particularly with fat-free mass. Difference in body size was consistent with the pharmacokinetics of lithium metabolism in children and adults. LITHIUM IN HIV/AIDS Manic symptoms may develop in the context of HIV psychosis or as a result of treatment with anti-retroviral agents such as zidovudine (AZT). Treatment: Lithium is preferable (beware risk of toxicity) since there is some evidence suggesting that sodium valproate may increase viral replication and reduce white cell count (WCC).