Rol of lithium in psychiatry osmanali


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Rol of lithium in psychiatry osmanali

  1. 1. Slide 1 Dr Mohd Osman Ali MBBS, DPM CONSULTANT PSYCHIATRIST Slide 2 Scheme of Presentation • Chemistry and Pharmacokinetics • Pharmacodynamics • Therapeutic indications • Precautions • Adverse reactions and Intoxication • Drug interactions • Lab monitoring • Dosage and administration Slide 3
  2. 2. Slide 4 • Chemistry • Absorption • Distribution and metabolism • The elimination half-life • Excretion Slide 5 Chemistry • It is a member of the group IA alkaline metals together with sodium, potassium, rubidium, cesium, and francium. • Lithium follows hydrogen and helium on the periodic table, – making it the third simplest element(atomic number 3, atomic weight 6.94) – and the first solid element. Slide 6 IN NORMAL HUMAN BEINGS • Trace amounts of lithium are present in food and water and hence in all living tissue. • Whether lithium is essential to normal human growth and development has not been established, and there is no evidence of a lithium deficiency state in humans. • Experimentally produced lithium deficiency in goats and rats led to reduced fertility, retarded development, and reduced longevity
  3. 3. Slide 7 Absorption • Rapidly • completely absorbed • serum concentrations peaking – in 1 to 1.5 hours with standard preparations – and in 4 to 4.5 hours with the slow and controlled-release forms. • Equilibrium is reached after 5 to 7 days of regular intake Slide 8 Distribution and Metabolism •NO clinically important protein-binding properties •NO metabolites Slide 9 THE RATE AND EXTENT OF ENTRY INTO TISSUES • thyroid and renal concentrations exceed serum level, whereas red blood cell, spinal fluid, and brain concentrations do not. • Lithium enters and leaves the central nervous system (CNS) or crosses BBB slowly,which may explain – why acute overdoses with relatively high blood levels are sometimes well tolerated – why clinical manifestations of chronic intoxications often persist long after blood levels have decreased substantially.
  4. 4. Slide 10 The Elimination Half-life • about 18 to 24 hours FACTORS INFLUENCING • Age of the patient considerably longer in the elderly because of the age-related decrease in GFR (and correspondingly shorter in youth for the opposite reason). • Duration of treatment half-life as evidenced by a small study that found it to be 1.3 days in those just starting treatment but 2.4 days in those treated for over a year. • Obesity based on the observation that clearance was almost 50 percent higher in obese subjects than in normal-weight volunteers. Slide 11 Excretion • almost entirely by the kidneys – although small amounts are also lost in sweat and feces • A substantial amount of filtered lithium is reabsorbed (primarily in the proximal tubules) – so that renal lithium clearance is about one fifth of creatinine clearance • Excretion is complex during pregnancy,excretion increases during pregnancy but decreases after delivery Slide 12
  5. 5. Slide 13 In an overview of possible mechanisms of action, Robert Lenox and Chang-Gyu Hahn concluded: “We are currently still at the stage of identifying the pieces of the lithium puzzle; within the next 50 years, we will be putting the puzzle together” Slide 14 ???? LITHIUM DEFICIENCY •NOT the cause of bipolar disorder. • The amounts required for its mood stabilizing effects exceed the trace amounts normally present in the body by about 100-fold. Slide 15 • extremely difficult to ascertain the key mechanism of action of lithium in regulating mood because – The ubiquitous nature of sodium in the humanbody, and its involvement in a wide range of biological process, – and the potential for lithium to alter these processes • Marmol F. lithium; bipolar disorder and neurodegenertive disease possible cellular mechanism of the therapeutic effects of lithium. Pro neur psychopharmacol biol psychiatry 2008;32:1761--71
  6. 6. Slide 16 Slide 17 • Ion transport theories • The neurotransmitter arena • Signal transduction pathways • Alteration of nuclear transcription factors and influence of gene expression. • Bipolarity virus Ion Transport Theories PERTURBATION OF SODIUM PUMP • make use of lithium's similarities to both monovalent (sodium, potassium) and divalent (calcium, magnesium) cations • neuronal transmembrane potential differences are maintained by the Na, K-ATPase pump (also known as the sodium pump), • perturbations of this system are felt to cause neurotransmitter aberrations that translate into mania and depression. Slide 18 MEMBRANE STABILISING ACTION • Because lithium crosses cell membranes by four independent mechanisms (sodium pump, sodium leak channel, sodium-lithium countertransport, and lithium-bicarbonate exchange) • Synapse-specific accumulation of lithium has been demonstrated in intracellular microdomains.
  7. 7. Slide 19 The Neurotransmitter Arena • Early investigations focused undue optimism on the fashionable neurotransmitters (serotonin, norepinephrine, dopamine, acetylcholine, γ-aminobutyric acid [GABA]) and found that lithium had diverse effects on them all. Slide 20 GLUTAMATERGIC EXCITOTOXICITY • Recent studies have implicated glutamatergic excitotoxicity in the pathophysiology of bipolar disorder, especially mania. MODULATION OF NMDA AND AMPA RECEPTORS • Some, but not all, research findings suggest that lithium's antimanic effect might be related to modulation of N-methyl-D-aspartate (NMDA) or amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors Slide 21 Signal Transduction Pathways POSTTRANSLATIONAL MODIFICATIONS OF G PROTEINS • there is evidence suggesting that “the effects of chronic lithium may in part be mediated through posttranslational modifications of G proteins that affect its coupling to receptor and/or second messenger systems.” • Both the phosphoinositide and adenylyl cyclase second-messenger systems are altered by lithium in many ways.The activity of lithium in the adenylyl cyclase second messenger system has generated a bimodal theory to explain its action
  8. 8. Slide 22 THE INOSITOL DEPLETION HYPOTHESIS • based on lithium's potent inhibition of inositol monophosphatase, leading to intracellular inositol depletion, • has been difficult to validate Slide 23 REDUCED HIPPOCAMPAL EXPRESSION OF PKC AND MARCKS • work done by Husseini Manji, Robert Lenox, and others found reduced hippocampal cell expression of two isozymes of PKC as well as a substrate of PKC known as myristoylated alanine-rich C kinase substrate (MARCKS) • effects shared with valproate Slide 24 Alteration of Nuclear Transcription Factors and Influence of Gene Expression. THE DNA BINDING ACTIVITY OF ACTIVATOR PROTEIN-1 (AP-1) • was increased by chronic lithium treatment, • as were protein levels of immediate-early genes, c-Fos and c-Jun • similar effects were also found with valproate.
  9. 9. Slide 25 INHIBITION OF GLYCOGEN SYNTHASE KINASE-3 (GSK3) • a protein kinase involved in several signal transduction cascades • Among its many activities, GSK-3 regulates phosphorylation of tau, – the microtubule-associated protein involved in the paired helical filaments of Alzheimer's disease. – Perhaps lithium may play a role in the treatment of that disease by inhibiting abnormal hyperphosphorylation of tau. Slide 26 ADDITIONAL REGULATORY FACTORS • that may play a role in the etiology and treatment of bipolar disorder include – brain-derived neurotrophic factor (BDNF), – extracellular signal-regulated kinase (ERK), – the neuroprotective protein Bcl-2, – and other members of the neurotrophin family. Slide 27 NEUROTROPIC AND NEUROPROTECTIVE ACTIVITY • Lithium also has both neurotropic and neuroprotective activity • Possibly through its effects on NMDA pathways • that may further extend its spectrum of use beyond bipolar disorder
  10. 10. Slide 28 • Literature pertaining to possible neuroprotective effects of lithium reports largely on either in vitro or animal studies. The clinical literature is dominated by reports of neurotoxicity Slide 29 Bipolarity Virus • Lithium is an effective treatment for two clinically episodic illnesses; namely genital herpes simplex and bipolar disorder.It does have well-documented inhibitory effects on herpes simplex viral replication • but whether it also inhibits a yet unidentified virus that causes bipolar disorder remains to be determined. • A more speculative but not implausible theory Slide 30
  11. 11. Slide 31 • Historical(gouty mania) • Well established (FDA-approved) • Reasonably well established • Evidence of benefit in particular groups • Anecdotal, controversial, unresolved, or doubtful • Non psychiatric uses Slide 32 well established (FDA-approved) Manic episode Bipolar maintenance therapy Slide 33 Bipolar Disorders-- Mania • Currently it is but one of many FDA-approved drugs for treating manic episodes, but it continues to be listed among the first choices. • in rx of mania it is limited by – Usually takes a week to achieve response and that the coadministration of antipsychotics may increase the risk of neuroloigical side effects – Monitoring can be problematic if the pt is uncooperative
  12. 12. Slide 34 ONSET OF ACTION OF ACTION OF LITHIUM • Its onset of action is relatively slow, with clinical improvement usually occurring over the first 1 to 3 weeks of treatment. • Although a small open study suggested that oral lithium loading might produce improvement in a few days, this approach has yet to be substantiated. Slide 35 • Instead, the concomitant use of a benzodiazepine or an antipsychotic drug is often necessary during the initial phase of treatment. – Among antipsychotics, atypicals have largely replaced conventionals in terms of preference. – Since disturbed sleep may ignite or fuel a manic episode, early treatment of insomnia with a sedative may be useful. Slide 36 RESPONSE OF LITHIUM TO ACUTE MANIA • The response rate of 79 percent in the initial research trials contrasts • with findings of less success when dealing with patients with –mixed or dysphoric mania, –rapid cycling, –comorbid substance abuse, –or organicity(encephalopathy etc ).
  13. 13. Slide 37 FDA-APPROVED ANTIMANIC ALTERNATIVES • include divalproex, carbamazepine, aripiprazole, olanzapine, quetiapine, risperidone , and ziprasidone. Combining lithium with one of these is a common practice. • in the United States, divalproex has become a preferred initial treatment for dysphoric or true mixed mania). • The effectiveness of lithium maintenance therapy is far betterestablished than for any other drug, which may sometimes weigh infavor of using lithium to treat the initial manic episode. Slide 38 Slide 39 Bipolar Disorders– Maintenance Therapy • Long-term treatment does not cure bipolar disorder. • Long-term treatment with lithium is an effective way to reduce the frequency, severity, and duration of manic and depressive episodes in patients with bipolar disorder. • Lithium was somewhat more effective against mania than against depression (although some would debate this). • Also effective treatment for persons with sever cyclothymic disorder
  14. 14. Slide 40 RESPONSE TO LITHIUM MAINTENANCE • Treatment response to lithium monotherapy is usually less than complete, and supplemental pharmacotherapies are often necessary either intermittently or continuously. • Nonetheless, there is growing evidence for a major benefit from long-term lithium therapy; namely, reduced mortality. Slide 41 FAVORABLE RESPONSEWork by Paul Grof and others • episodic course with euthymic intervals, • and the absence of rapid cycling were the main predictors. Slide 42 LESS THAN IDEAL RESPONSE factors have been associated Mixed or dysphoric mania rapid cycling (four or more episodes per year), many prior episodes, poor interepisode functioning, an episode pattern of depression-maniaeuthymia, • comorbid substance abuse • and comorbid personality disorder. • • • • •
  15. 15. Slide 43 ANTISUICIDAL EFFECTS OF LITHIUM • the antisuicidal effect of lithium extends beyond its mood stabilizing property (the beneficial role of psychosocial support could also be a contributing factor). SOP10th -- Reduces incidence by six fold or seven fold • In general, bipolar disorder carries with it an increased risk of premature death, particularly but not entirely from suicide • Studies comparing mortality rates in lithium-treated patients to the general population, to patients following discontinuation of lithium, and to patients treated with alternative prophylactic medications all support the mortality-lowering and suicide-reducing effect of lithium Slide 44 • Lithium reduced by 80% the risk of both attempted and completed suicide – Baldessarini RJ et al. decreased risk of suicides and attempts during long-term lithium treatment: a metaanalytical review. Bipolar disorder 2006;8:625– 39 • Studies comparing lithium and divalproex – Goodwin FK et al. suicide risk in bipolar during treatment with lithium and divalproex. JAMA2003;290: 1467--73 – Coolins JC et al. divalproex, lithium and suicide among medical patients with bipolar disorder. J affect disorder 2008;23--8 Slide 45 • The mechanism of this protective effect is unknown • In patients with unipolar depression, lithium also seems to protect against suicide ; the effect size being similar to that found in bipolar illness – Guzzetta F et al. lithium reduces suicide risk in recurrent major depressive disorder. J clin psychiatry 2007;68:380--3
  16. 16. Slide 46 WHEN TO BEGIN LONG-TERM LITHIUM TREATMENT • Just exactly when has not been fully resolved, • although most recommendations suggest earlier rather than later—possibly after only one episode of mania and certainly after two. • There is growing concern that episodes beget episodes (perhaps a form of kindling or behavioral sensitization), and that each episode increases the likelihood of the next and may shorten the interval to the next; hence, the recent trend toward earlier initiation of maintenance therapy. Slide 47 • Obviously, many individual factors must be taken into consideration, including – – – – – the abruptness, severity, and frequency of episodes; the presence of risk factors; and attitudes toward medication. • Early initiation of maintenance therapy may benefit many patients at the expense of some patients being treated unnecessarily • The maximum benefits of lithium maintenance may not be immediate; with continued treatment, relapses sometimes become less severe and less frequent. Slide 48 SOP10TH • • • lithium maintenance is almost always indicated after the second episode of bipolar 1 disorder depression or mania And should be considered after first episode for – Adolescence – For the persons who have family history of bipolar 1 disorder Others who benefit from lithium maintenance are – Those who have poor support system – Had no precipitating factor for the first episode – Or had a first episode of mania
  17. 17. Slide 49 Slide 50 Slide 51 TOLERANCE TO LITHIUM • Some patients appear to develop a tolerance to lithium after several years of successful use; • this tolerance can sometimes be overcome by the addition of divalproex, carbamazepine, lamotrigine, or an atypical antipsychotic BREAKTHROUGH DEPRESSION AND MANIA • Just as breakthrough depression may respond to a temporary increase in serum lithium concentration, so too may breakthrough mania DISCONTINUATION OF SUCCESSFUL LITHIUM THERAPY • the risk of recurrence increases substantially • In addition, rapid discontinuation of lithium appears to be associated with a rebound phenomenon characterized by increased risk of early recurrence, especially mania.
  18. 18. Slide 52 LITHIUM-DISCONTINUATION–INDUCED REFRACTORINESS. • Some patients, approaching 15 percent, who had responded well to lithium prophylaxis may not respond again when lithium is reintroduced after a failed discontinuation trial. • A decision to discontinue successful lithium maintenance should not be taken lightly, but rather must be weighed carefully against the continued risk of adverse effects and toxicity. Slide 53 reasonably well established Bipolar disorder Depressive episode Bipolar II disorder Rapid-cycling bipolar I disorder Cyclothymic disorder Major depressive disorder Acute depression (as an augmenting agent) Maintenance therapy Schizoaffective disorder Slide 54 Bipolar Disorders-- Depression • Although lithium is not approved by the FDA for the acute treatment of bipolar depressive episodes (in contrast to quetiapine and olanzapine/fluoxetine combination [Symbyax]), • there is sufficient research to support its effectiveness as a first-line choice either alone or for more severe depressions in combination with an antidepressant or another medication. • Therapeutic blood concentrations have not been well established for the antidepressant effects of lithium but appear to be in the same general range as for mania.
  19. 19. Slide 55 ROLE OF LAMOTRIGINE • Recent studies of lamotrigine (Lamictal) have questioned its effectiveness as monotherapy for bipolar depression, • and the effectiveness of other anticonvulsants such as carbamazepine, oxcarbazepine (Trileptal), and divalproex for treating bipolar depression is not well established. • Since lamotrigine is beneficial for prevention of recurrent bipolar depression with long-term treatment, combining it with lithium has considerable appeal. Slide 56 ROLE OF ANTIDEPRESSANTS • Treating bipolar depression with a conventional antidepressant alone does not protect against mania and may even precipitate mania or rapid cycling. • Consequently, the presence of a mood stabilizer is a necessity in all but occasional low-risk bipolar II patients. • Although tricyclic drugs can be effective, they have fallen by the wayside because of poor tolerability and higher switch rates to mania than newer antidepressants. • Preferred antidepressants for bipolar depression are bupropion, SSRIs,and venlafaxine, with an edge toward bupropion in all but the most severe cases. • All in all, the role that antidepressants should or should not play in the treatment of bipolar disorder remains a matter of great debate Slide 57 ROLE OF ECT • is an effective treatment for bipolar depression, although it tends to be used only after medications have failed. • Concern has been expressed that the presence of lithium during ECT increases the risk and severity of cognitive dysfunction, but whether this is true remains controversial.
  20. 20. Slide 58 DURATION OF ANTIDEPRESSENT AND LITHIUM COMBINATION • if an antidepressant is combined successfully with lithium, • it was once recommended that it be discontinued shortly after remission to reduce the risk of antidepressant-induced mania or rapid cycling. • In practice, however, some patients seem to both require and tolerate the long-term use of lithium and an antidepressant. • At present, some experts suggest continuing the antidepressant for 2 to 6 months after remission of a first episode of bipolar depression. Slide 59 BREAKTHROUGH DEPRESSION • If breakthrough depression occurs during lithium maintenance, – lithium-induced hypothyroidism, – poor compliance, – and substance abuse must be considered as possible causes or contributors. • If there is a margin of safety and tolerability, increasing the serum lithium level may be sufficient to bring the episode under control. Slide 60 • even if results of thyroid function testing are within normal limits, supplementing with thyroid hormone may be of value. • There is some evidence that bipolar depression responds more slowly to antidepressant treatment in patients who have a lower free thyroxine index (FTI) and higher thyroid-stimulating hormone (TSH) levels, even within the range of normal. • If optimizing the lithium blood level is ineffective, an antidepressant, a second mood stabilizer, or an atypical antipsychotic could be added.
  21. 21. Slide 61 Major Depressive Disorder • Although episodes of major depressive disorder may respond to lithium alone, traditional antidepressant medications are considerably more effective and are the preferred treatment. • The major value of lithium in major depressive disorder patients with acute depression is as an augmenting agent when antidepressants alone have been ineffective. Slide 62 Slide 63 AUGMENTATION OF ANTIDEPRESSANTS • On average, about 50 percent of patients respond when lithium carbonate, usually 300 mg three times daily (less in the elderly), is added to a wide variety of antidepressant drugs. • Occasionally, a dramatic response is noted in 24 to 48 hours, but improvement is more likely to occur gradually over several weeks. • Benefit has been reported with most all antidepressants, but evidence is most convincing with tricyclics. • When effective, augmentation should be maintained for at least 12 months. • research support for a true augmenting interaction is quite persuasive. • Indeed, most studies have found lithium to be more effective than placebo and as effective as antidepressant drugs for the long-term management of major depressive disorder.(esp those with marked cyclicity) – This may reflect the conceptualization that highly recurrent major depressive disorder and bipolar disorder are both components of manic-depressive illness.
  22. 22. Slide 64 • Lithium has not, however, demonstrated clear advantages over conventional antidepressant drugs, and since long-term treatment is most likely to involve the drug that ended the acute episode (an antidepressant), lithium maintenance for major depressive disorder is likely to be reserved for antidepressant treatment failures. – On the other hand, a recent meta-analysis found support for antisuicidal effects of lithium in patients with recurrent major depressive disorder. Slide 65 Evidence of benefit in particular groups Schizophrenia Aggression (episodic), explosive behavior, and self-mutilation Conduct disorder in children and adolescents Mental retardation Cognitive disorders Prisoners Slide 66 Schizoaffective Disorder and Schizophrenia • lithium is generally accepted to be of value for treating this condition, especially in combination with antipsychotic drugs, and especially if the affective component is prominent. – In general, the less affective and the more schizophrenic an illness is, the less likely it is to respond to lithium
  23. 23. Slide 67 • The addition of lithium to an antipsychotic agent – remains a treatment strategy for antipsychoticresistant schizophrenia, although the availability of atypical antipsychotics makes this less necessary – In addition, while several small early studies suggested benefit from lithium augmentation of antipsychotic medication, more recent data have been less convincing. – Should there be a coexisting mood disorder, lithium might play a more prominent role. Slide 68 Aggression • Lithium appears to have antiaggressive effects independent of its mood-stabilizing action. • Behavioral dyscontroland self-mutilation in intellectual disabled patients have also been successfully treated with lithium • No work has been done to evaluate the effect of lithium in those patients defined by DSM-IV-TR as having intermittent explosive disorder. Slide 69 • Aggressive outbursts are also treated with medications such as anticonvulsants, βadrenergic receptor antagonists, benzodiazepines, buspirone (BuSpar), antipsychotics, and antidepressants. – The relative ranking of lithium among those other drugs must be determined on an individual basis.
  24. 24. Slide 70 OTHER USES • To both treat and prevent steroid induced psychosis • To raise the white blood cell counts in pts receiving clozapine Slide 71 Anecdotal, controversial, unresolved, or doubtful Slide 72 • Alcohol and other substance-related disorders – – Cocaine abuse Substance-induced mood disorder with manic features – that found reduced alcohol intake in rodents receiving lithium. Efforts to establish lithium as a useful treatment for alcoholism have been largely unsuccessful – Although not all research reports have been that discouraging, lithium is unlikely to play a major role in the treatment of alcoholism
  25. 25. Slide 73 • Anxiety disorders Obsessive-compulsive disorder(ineffective) – Phobias – Posttraumatic stress disorder – • Attention-deficit/hyperactivity disorder • Eating disorders Anorexia nervosa – Bulimia nervosa – • Impulse-control disorders Slide 74 • Klein-Levin syndrome • Mental disorders due to a general medical condition (e.g., mood disorder due to a general medical condition with manic features) • Periodic catatonia • Periodic hypersomnia Slide 75 • Personality disorders (e.g., antisocial, borderline, emotionally unstable, schizotypal) – it is likely that a comorbid mood disorder has responded followed by indirect improvement in personality – Today, the substantial mood component of borderline personality disorder suggests a role for lithium in its treatment, but controlled trials have not been conducted • Premenstrual dysphoric disorder • Sexual disorders – – Transvestic fetishism Exhibitionism Pathological hypersexuality
  26. 26. Slide 76 Slide 77 • children and adolescents • elderly patients • pregnant patients • Lactating patients • medically ill patients • rapid cycling patients Slide 78 Children and Adolescents • lithium is FDA-approved for treating mania in adolescents (ages 12 years and older). • The range of serum lithium concentrations in adolescents is similar to that in adults (although its elimination half-life may be shorter) • and the likelihood of responding appears the same.
  27. 27. Slide 79 THE ADVERSE EFFECT PROFILE OF LITHIUM IN CHILDREN • is also the same across age groups, • although in view of adolescent concern about body image,adverse events such as acne and weight gain may be poorly tolerated. • Also, nontoxic cognitive dulling induced by therapeutic amounts of lithium may impact negatively on academic performance. Slide 80 WHEN TO BEGIN LONG-TERM LITHIUM THERAPY IN CHILDREN AND ADOLESCENTS • is an even more difficult decision when treating young patients than when treating adults. • The markedly disruptive effects of episodes in youth and the highly recurrent nature of bipolar disorder must be balanced against the potentially deleterious adverse effects of long-term lithium. • The following factors may be predictive of a bipolar outcome and influence early treatment with lithium or another mood stabilizer: – rapid onset with psychosis and psychomotor retardation, – family history of bipolar disorder, and – antidepressant-induced hypomania Slide 81 Elderly Patients • In the absence of organicity and substance abuse, most evidence suggests that advanced age alone does not compromise responsiveness to lithium. FACTORS COMPLICATING IN ELDERLY • • • • associated medical illnesses and medications, special diets, age-related reduction in GFR, • and increased sensitivity to adverse effects.
  28. 28. Slide 82 SERUM LITHIUM LEVELS IN ELDERLY • Whether the elderly as a group respond to lower serum concentrations of lithium than do their younger counterparts is not known. – Increased sensitivity to adverse effects and toxicity confine many elderly patients to relatively low doses and blood concentrations, which may prevent them from benefiting from the drug. However, this is not always the case Slide 83 THE ELIMINATION HALF-LIFE OF LITHIUMIN ELDERLY • in increases with age, and the time required to reach steady state is much longer in the elderly. – If lithium is stopped, serum levels fall more slowly and the resolution of adverse effects and toxicity may be prolonged THE PUTATIVE NEUROPROTECTIVE EFFECTS OF LITHIUM • have practical utility in this population remains open to question. Slide 84 • in general, the elderly – should be started on lower-than-usual dosages, with dosage changes occurring less frequently than in younger patients – With appropriate monitoring and compliant patients, lithium use in the elderly can be both safe and effective.
  29. 29. Slide 85 Pregnant Patients • FDA pregnancy category D • drugs for which there is evidence of human fetal risk, but whose potential benefits may outweigh the risk in some pregnant women. Slide 86 CARDIOVASCULAR ANOMALIES • incidence of Ebstein's anomaly is between 1 and 2 per 1,000 which is 10 to 20 times greater than in the general population. • fetal echocardiography is advised to screen for cardiovascular malformations in women exposed to lithium during the first trimester of pregnancy. • Although the teratogenic risk of lithium is still greater than that found in the general population, it is lower than that posed by carbamazepine and valproate. Slide 87 POLYHYDRAMNIOS • in a pregnant woman taking lithium was ascribed to lithium-induced fetal polyuria.
  30. 30. Slide 88 Slide 89 • Physiological changes accompanying pregnancy alter maternal lithium metabolism • Complications of pregnancy, such as hypertension and edema and their treatments, may further complicate lithium therapy. • Following delivery, the altered renal physiology of pregnancy returns rapidly to normal. – These factors and their variability among individual patients dictate that lithium use during pregnancy be closely supervised. DURING PREGNANCY • Fetal and maternal blood concentrations are similar, so women should receive minimum effective dosages. Slide 90 SHORTLY BEFORE DELIVERY. • To reduce the risk of toxicity in the newborn, clinicians should markedly reduce or possibly temporarily discontinue the drug • In view of evidence that abrupt or rapid discontinuation of lithium is associated with a high risk of relapse (which may be increased further postpartum), dosage reduction rather than discontinuation may be more appropriate as delivery approaches.
  31. 31. Slide 91 Slide 92 FOLLOWING DELIVERY • Full prophylactic concentrations should be reestablished • because this is a time of great vulnerability to recurrence. Lactating Patients • Because lithium appears in breast milk and in the blood of breast-fed babies, the American Academy of Pediatrics Committee on Drugs feels that lithium should be used with caution in nursing mothers. • The merits of breastfeeding are considerable, and actual reports of infant lithium toxicity are limited to one or two cases; • consequently, in some situations the benefits may outweigh the risks. • Signs of lithium toxicity in infants include lethargy, cyanosis, abnormal reflexes, and sometimes hepatomegaly Slide 93 Medically Ill Patients • Untreated or inadequately treated mania or depression can adversely affect a medical illness (e.g., mania and congestive heart failure) and decrease treatment adherence, • and lithium may be more difficult or impossible to use in the presence of a medical illness (e.g., severe renal disease). • Also, because medically ill patients are receiving other medications, the risk of adverse drug interactions is increased.
  32. 32. Slide 94 LOW-SODIUM DIETS • result in increased serum lithium concentrations and may cause lithium intoxication unless the dosage of lithium is reduced. DIETS THAT SEVERELY RESTRICT FLUID INTAKE • place patients at risk for dehydration and subsequent lithium intoxication. • Should be used with caution in diabetic person, who should monitor their blood glucose concentratios carefully to avoid diabetic ketoacidosis Slide 95 Rapid Cycling Patients • Rapid cycling – has been defined as four or more mood disorder episodes per year. – Up to 20 percent of bipolar disorder patients are rapid cyclers and the majority of them are women. – Rapid cycling may not be a persistent condition in many who experience it. • Ultra-rapid cyclers – have 24- to 48-hour cycles, – and the concept of ultra-ultra rapid cycling has been introduced to describe patients with frequent mood shifts within a 24-hour period. Slide 96 • Risk factors associated with rapid cycling – a depression-hypomania course, – antidepressant drug therapy (some controversy remains about this). Also, because antidepressants may induce rapid cycling, merely discontinuing the antidepressant agent may be sufficient to slow the cycling pattern (although at times a rather nasty depression is the result). – thyroid abnormalities, – and neurological disease.
  33. 33. Slide 97 RESOPONSE OF RAPID CYCLERS TO LITHIUM • less responsive to lithium • Prior treatment with antidepressant drugs may predict a poorer response to lithium. Slide 98 WHAT TO DO • Correcting thyroid abnormalities is an important aspect of treating rapid cycling. – Preliminary research suggests that hypermetabolic doses of thyroid hormone may be useful in dealing with treatment-resistant rapid cycling. • If lithium alone is ineffective, – treatment considerations include some anticonvulsants (particularly lamotrigine and valproate) either alone or combined with lithium. – Atypical antipsychotics are additional considerations, as is ECT in more extreme cases. Slide 99
  34. 34. Slide 100 • Neurological • Endocrine • Cardiovascular • Renal • Dermatological • Gastrointestinal • Miscellaneous Slide 101 Slide 102 • Adverse effects are to be expected during lithium therapy. • Fewer than 20 percent of patients have no adverse effects, but only about 30 percent have more than minor complaints • Most side effects are dose related Neurological Adverse Effects • Benign, nontoxic: – Dysphoria, – lack of spontaneity, – slowed reaction time, – memory difficulties • Tremor: – Postural, – occasional extrapyramidal
  35. 35. Slide 103 • Toxic: – – – – Coarse tremor dysarthria, ataxia, neuromuscular irritability, seizures, coma, death • Miscellaneous: rarely with – – – – – peripheral neuropathy, downbeat nystagmus, benign intracranial hypertension (pseudotumor cerebri), a myasthenia gravis–like syndrome, and lowering of the seizure threshold. • Creativity has been variously enhanced, impaired, and unaltered by lithium therapy. Slide 104 BENIGN, NONTOXIC NEUROLOGIC ADVERS EFFECTS • These are – Dysphoria, – lack of spontaneity, – slowed reaction time, – intellectual inefficiency, – and spotty impairment of memory. • Although these complaints may be subtle, they are a common cause of poor compliance. Slide 105 • The following must also be considered as possible causes of these complaints: – Breakthrough depression, – lithium-induced hypothyroidism or hypercalcemia, – other illnesses, – and other drugs. • Single daily dosing at bedtime or a dosage reduction may be helpful, although switching to another mood stabilizer may be necessary.
  36. 36. Slide 106 TREMOR • Postural, occasional extrapyramidal • The most common tremor associated with lithium use is a benign postural tremor with a frequency of 8 to 12 Hz in the hands (which is similar to the tremor seen with valproate). • Because the tremor worsens during activities requiring fine motor control, it can be socially embarrassing and occupationally troublesome. • With long-term lithium therapy, a tremor with parkinsonian characteristics may occur occasionally. Slide 107 MANAGEMENT OF TREMOR • A nontoxic tremor often improves spontaneously, • but if it does not, benefit may be obtained from – – – – – dose reduction, use of a slow-release lithium preparation, elimination of dietary caffeine, discontinuation of other medications, and treatment of associated anxiety. • Medications useful in treating lithium tremor include – β-adrenergic receptor antagonists such as propranolol (Inderal), – as well as primidone (Mysoline), – and possibly gabapentin (Neurontin). Slide 108 IMPORTANCE OF TREMOR • A worsening of tremor at any time during the course of lithium therapy may be an indication of impending lithium intoxication, • and COARSE tremor should be considered due to lithium toxicity until proven otherwise.
  37. 37. Slide 109 Endocrine Adverse Effects • Thyroid: – Goiter, hypothyroidism, – exophthalmos, – hyperthyroidism (rare) • Parathyroid: – Hyperparathyroidism, – adenoma Slide 110 GOITER, HYPOTHYROIDISM TRANSIENT MILD ABNORMALITIES • are common early in the course of lithium treatment • but are usually of little or no clinical consequence. normalize without treatment. • more than usually susceptible are – Women, esp during first two years of treatment – those with preexisting thyroid dysfunction – and those from iodine deficient areas, . • Slide 111 Among lithium's many effects on thyroid function, most importantly it impedes the release of hormone from the gland SUBCLINICAL HYPOTHYROIDISM • elevated TSH, normal free thyroxine • is considerably more common than clinical hypothyroidism. • Nonetheless, subclinical hypothyroidism may not be asymptomatic, and it may be associated with a slower response of bipolar depression to conventional treatment; consequently it may require treatment with supplemental thyroxine.
  38. 38. Slide 112 CLINICAL HYPOTHYROIDISM • occurs in at least 4 percent of patients taking lithium • Once diagnosed, it can be treated with supplemental levothyroxine (Synthroid) at a dosage that returns the TSH concentration to normal. Slide 113 Slide 114 THE GOITER • has been described in about 5 percent of patients taking lithium (prevalence figures vary widely) • is rarely of cosmetic or obstructive importance; MONITORING FOR THYROID FUNCTIONS • Baseline assessment (including antithyroid antibody titers) and periodic monitoring of thyroid function is an integral part of lithium therapy • usually measurement – of serum TSH concentration – with or without triiodothyronine [T3] and thyroxine [T4] concentrations. • Whether it is done routinely (every 6 or 12 months) or only when clinical suspicion is aroused is a matter of preference. • Lithium induced hypothyroidism should be considered when evaluating depressive episode during lithium therapy
  39. 39. Slide 115 EXOPHTHALMOS, HYPERTHYROIDISM • Whether these occur more often than in the general population remains a matter of controversy. • One study implicated lithium-induced silent thyroiditis as a potential cause of thyrotoxicosis Slide 116 HYPERPARATHYROIDISM AND HYPERCALCEMIA • several possible mechanisms • – antagonism of the calcium sensing receptor, direct stimulation of parathyroid hormone production, and decreased renal calcium excretion Hypercalcemia is usually mild, but there have been reports of surgery being required to treat parathyroid hyperplasia or adenoma • Clinical consequences of chronically increased serum calcium include– renal stones, osteoporosis, dyspepsia, hypertension and renal impairment • Some authorities advise baseline and periodic monitoring of serum calcium levels. Slide 117 Cardiovascular Adverse Effects • Benign T-wave changes, are common during lithium therapy and are of no clinical consequence. – Resemble those of hyopokalemia on the ECG – Caused by the displacement of intracellular potassium by the lithium ion • can impair sinus node function, – Contraindicated in persons with sick sinus syndrome – Cause sinus dysrhythmias, sometimes associated with syncopal episodes, have been reported in a few patients.
  40. 40. Slide 118 Slide 119 • Varying degrees of heart block and bradyarrhythmias as well as QTc prolongation and T-wave inversion have been reported during lithium intoxication and occasionally during its therapeutic use. • Lithium does not have clinically important effects on blood pressure. • Although the drug is not contraindicated in the presence of cardiovascular disease, it should be used with caution. – Low-salt diets, – certain diuretics, – angiotensin-converting enzyme inhibitors, – angiotensin II receptor type-1 antagonists, – fluid-electrolyte imbalances, – and impaired renal function • all predispose to lithium toxicity. Slide 120 Renal Adverse Effects • • • • polyuria (nephrogenic diabetes insipidus), Concentrating defect, morphological changes, occasional--reduced GFR,nephrotic syndrome, renal tubular acidosis – Progression of renal insufficiency has been described despite discontinuation of lithium, but it is not clear if this suggests an alternative etiology or if lithium has ignited an irreversible event.
  41. 41. Slide 121 MONITORING FOR RENAL ADVERSE EFFECTS • For most patients, – the periodic measurement of serum creatinine, – a urinalysis, – and a clinical estimate of urine volume will suffice. • Equation-based estimations of GFR are in common use but may be inaccurate at higher levels of kidney function. • If appropriate, a 24-hour urine volume, protein, and creatinine clearance will provide more comprehensive information. Slide 122 POLYURIA (nephrogenic diabetes insipidus) • Them most common adverse effect with seconday polydysia and also the most clinically troublesome renal effect of lithium. • a 24-hour urine volume of more than 3 L (1 to 2 L is normal) has been reported in as many as 35 percent of patients taking lithium. • Lithium increases urine volume primarily by inhibiting the effect of antidiuretic hormone on the kidneys, – although additional renal (including disruption of the aquaporin-2 shuttle) and CNS mechanisms have been identified. Slide 123 • The effect is usually reversible in the short to medium term but may be irreversible after longterm (>15 years) • When severe, polyuria can be – socially and occupationally compromising; – a cause of insomnia, – weight gain (through consumption of high-calorie beverages), – poor nutrition, – and noncompliance; – and potentially dangerous if dehydration occurs. • Polyuria does not always resolve following discontinuation of lithium.
  42. 42. Slide 124 TREATMENT CONSIDERATIONS FOR POLYURIA adequate fluid replacement, Shifting to single daily dosing using the lowest effective dosage, and counteractive medications such as thiazides or potassium sparing diuretics, or indomethacin (Indocin). • Amiloride (Midamor) or an amiloridehydrochlorothiazide combination (Moduretic) is preferred to minimize the risk of hypokalemia. • • • • – Whether single-daily dosing is beneficial remains controversial, as do treatments such as inositol, potassium supplementation, and desmopressin (DDAVP). – Slide 125 CONCENTRATING DEFECT • In the majority of patients, lithium impairs renal concentrating ability, which in itself is of no clinical importance. • The concentrating defect is not always reversible after lithium discontinuation, suggesting that both functional and structural changes have occurred in the distal tubules and collecting ducts. Slide 126 MORPHOLOGICAL CHANGES • The most common finding is a nonspecific interstitial fibrosis,-- the most serious renal adverse effect and associate with chronic use • although a lithium-distinctive microcystic lesion has also been described. • In the absence of lithium intoxication and renal insufficiency, the morphological changes attributed to lithium tend to be mild, especially when compared with appropriately selected controls.
  43. 43. Slide 127 Dermatological Adverse Effects • the first occurrence or worsening of – acne, – psoriasis, – and follicular keratosis, • scattered reports of rashes of various types, • and hair loss that is only occasionally related to lithium-induced hypothyroidism. • If tetracycline is used for rx of acne it can cause lithium retention Slide 128 Gastrointestinal Adverse Effects • common but usually mild – Appetite loss, – nausea, – vomiting, – diarrhea • Severe gastrointestinal symptoms – may portend impending lithium intoxication. Slide 129 SOP 10th • These can be diminished by – Dividing the dosage – Administration of lithium with food – Or switching to another lithium preparation • The lithium preparation – least likely to cause diarrhea is lithium citrate – Because ofSome preparations contain lactose – More With slow release preparations , because of unbsorbed medication in the lower part of GI, – may experience less with standard release preparations – Diarrhoea may respond to loperamide, bismuth subsalicylate, or diphenoxylate with atropine
  44. 44. Slide 130 Hematological Effects • The most common hematological effect of lithium is – a benign, reversible, and usually mild granulocytosis – induced by stimulation of granulocyte production. • An increase in platelet count is noted occasionally, • but there are no clinically important effects on red blood cell count. Slide 131 Weight Gain • Weight gain is a common adverse effect of lithium • and may be due to – the drug's complex effects on carbohydrate metabolism. – Other possible causes include lithium • induced hypothyroidism, • fluid retention, • and increased caloric intake from thirst-quenching beverages. Slide 132 Sexual Adverse Effects • Sexual dysfunction, including decreased libido and erectile difficulties, has been attributed to lithium, • but well-documented cases are quite uncommon.
  45. 45. Slide 133 Slide 134 • Factors associated with toxicity • Symptoms and signs • Toxic Serum lithium levels • treatment Slide 135 Factors Associated with Toxicity excessive intake (accidental or deliberate), reduced excretion, kidney disease, Changes in sodium levels-low-sodium diet,dehydration drug interaction, and individual sensitivity (the elderly and the organically impaired). • Antipsychotic drug-induced sedation impaired ability to replace fluids • Uncommon physical illness– Addisons disease • • • • • •
  46. 46. Slide 136 Toxic Serum Lithium levels • There is no well-demarcated below which intoxication never occurs and above which it is inevitable. – Severe toxicity has been described in patients whose serum concentrations were within the socalled therapeutic range of .5 to 1.5 mEq/L. • In general, however, the higher the concentration and the longer the exposure, the more serious the intoxication Slide 137 SOP 10th • mild to moerate intoxication(1.5-2 meq/l) • moderate to severe intoxication (2-2.5meq/ lit) • severe lithium intoxication(>2.5 meq/l) Slide 138 MAUDSLEY 10TH • Toxic effects reliably occur at levels > 1.5 m mol/L – Usually consists of gastrointestinal effects – increasing anorexia, nausea and diarrhoea – and CNS effects– muscle weakness, drowsiness, ataxia, course tremor and muscle twitching • Above 2 m mol /L – Increased disorientation and seizures usually occur which can progress to coma and ultimaley death • Individuals vary in their susceptibility to symptoms of toxicity
  47. 47. Slide 139 Symptoms and signs NEUROTOXICITY • Lithium intoxication is primarily a neurotoxicity • that can lead to death • or permanent neurological damage often cerebellar as characterized by – dysarthric speech, – tremor, – and wide-based gait. • Cardiovascular, gastrointestinal, and renal manifestations may also be present. Slide 140 EARLY CLINICAL MANIFESTATIONS • gastrointestinal upset, • dysarthria, • ataxia, • and coarse tremor. OMINOUS FINDINGS • impaired consciousness, • neuromuscular irritability (fasciculations, myoclonus), • seizures, • and coma Slide 141 MILD TO MOERATE INTOXICATION(1.5-2 mEq/L) • GASTROINTESTINAL – Vomiting – Abdominal pain – Dryness of mouth • NEUROLOGICAL – – – – – – Ataxia Dizziness Slurred speech Nysytagmus Lethargy or exciteent Muscle weakness
  48. 48. Slide 142 MODERATE TO SEVERE INTOXICATION (2-2.5meq/ lit) GASTROINTESTINAL Anorexia Persistent nausea and voiting NEUROLOGICAL Blurred vision muscle fasiculations Clonic limb movements Hyperactive deep tendon reflexes Choreoatheoid movements Convulsions Delirium Syncope EEG changes Stupor Coma Circulatory failure Slide 143 SEVERE LITHIUM INTOXICATION(>2.5 MEQ/L) • • • • Generalized convulsions Oliguria Renal failure death Slide 144 • Some cases of lithium intoxication have resembled – Creutzfeldt-Jakob disease, – nonconvulsive status epilepticus, – or neuroleptic malignant syndrome. • Absorption can be delayed substantially if slow-release preparations are involved.
  49. 49. Slide 145 Treatment • is directed at the removal of lithium from the body. • In mild cases, nothing more may be necessary than discontinuation of intake. • Dehydration treated Slide 146 GASTRIC LAVAGE AFTER AN OVERDOSE • is indicated and may have to be repeated. • Although activated charcoal is not helpful following an acute lithium overdose, • preliminary reports using polystyrene sulfonate (Kayexalate), a cation exchange resin, • or whole bowel irrigation with polyethylene glycol solution (GoLYTELY) have been promising. Slide 147 Rx OF MILD TO MODERATE TOXICITY • In the presence of normal renal function, often responds to correcting dehydration and maintaining proper fluid and electrolyte balance. • Whether forced diuresis provides additional benefit is open to debate.
  50. 50. Slide 148 Rx OF SEVERE INTOXICATION (> 3 m eq/ lit) • Hemodialysis is the treatment of choice for severe intoxication (peritoneal dialysis is considerably less efficient) • Lithium is removed effectively by dialysis because it is water soluble, unbound to plasma protein,without metabolites, and of simple chemical structure (an element). Slide 149 • Redistribution of lithium from tissues to blood after dialysis usually results in a rebound increase in its blood level; this may necessitate further dialysis. – Hemodialfiltration has also been used, sometimes in conjunction with hemodialysis tominimize the likelihood of rebound. • Because of the drug's tissue-toxic effects and its gradual removal from the CNS, clinical improvement may lag many days behind the lowering of serum concentration. Slide 150
  51. 51. Slide 151 • ACE inhibitors and Angiotensin II receptor (AT-1)antagonists • Diuretics • NSAIDs • Calcium channel inhibitors • Miscellaneous drugs • Psychiatric drugs – Antipsychotics, – Antidepressan – Anticonvulsantsts – and ECT Slide 152 • Most clinically significant interactions are with drugs that alter renal sodium handling Slide 153 Lithium ₊ ACE inhibitors or Angiotensin II antagonists • ACE inhibitors– captopril, cilazapril, enalapril,fosinopril, imidapril, lisinopril, moexipril, perinopril, quinapril, ramipril and trandolapril • Angiotensin receptor antagonists– candesartan, eposartan, irbesartan, losartan, olmesertan, telmesartan, and valsartan • both of these drug classes are used extensively to treat cardiovascular disease,
  52. 52. Slide 154 • Ace inhibitors can reduce thirst which can lead to – mild dehydration and increase renal Na loss leading to – increased Na reabsorption by the kidney leading to an increase in lithium plasma levels • The magnitude of this effect is variable; from no increase to a fourfold increase • The full effect can take several weeks to develop • In elderly, ACE inhibitors increase seven fold the risk of hospitalisation due lithium toixicity • ACE inhibitors can also precipitate renal failure Slide 155 Lithium ₊ Diuretics • Diuretics can reduce the renal clearance of lithium, the magnitude of this effect being greater with thiazide than loop dieuretics • Thiazides – Drugs are bendroflumethiazide, chlorthalidone, cyclopenthiazide, idapamide, metolazone, and xipamide Slide 156 – Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed – Magnitude of rise is unpredictable and can vary from 25% to 400% – Well-documented reduced renal lithium clearance and increased serum concentration. – Toxicity reported – If a thiazide is prescribed, lithium dosage reduction is often necessary. – If a thiazide is discontinued, lithium dosage may need to be increased to avoid subtherapeutic levels
  53. 53. Slide 157 • Loop – Drugs are– bumetamide,furosemide, and torsemide – lithium clearance unchanged (some case reports of increased lithium concentration). – Pt are on low sodium diet this may inrease the toxicity – Loop diuretics are safer any effect will be apparent in the first month • Potassium-sparing – Limited data, may increase lithium concentration. Slide 158 • Osmotic (mannitol, urea) – Increase renal lithium clearance and decrease lithium concentration • Xanthine (aminophylline, caffeine, theophylline) – increase renal lithium clearance and decrease lithium concentration. • Carbonic anhydrase inhibitors – Increase renal lithium clearance (acetazolamide) Slide 159 • Because diuretics are often given to patients who are medically ill with unstable fluidelectrolyte status, interactions with lithium may not be predictable, and close monitoring is advised.
  54. 54. Slide 160 Lithium ₊ NSAIDs • Inhibit synthesis of renal prostaglandins, thereby renal blood flow and possibly increasing renal re-absorption of sodium and therefore lithium • reduce renal lithium clearance and increase the serum lithium concentration – in a way that is clinically important and potentially dangerous. Slide 161 • Among the drugs that cause this interaction are – indomethacin (Indocin), – phenylbutazone (Butazolidine), – diclofenac (Voltaren), – ketoprofen (Orudis), – meloxicam (Mobic), – oxyphenbutazone (Tandearil), – ibuprofen (Motrin, Advil, Nuprin), – piroxicam (Feldene), – and naproxen (Naprosyn). Slide 162 • Aspirin and possibly sulindac (Clinoril) appear to be exceptions. • The newer cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex) and rofecoxib (Vioxx, no longer available), are no exception. • Risk factors include – high doses of the anti-inflammatory drug, increased age, – and renal impairment. • Because many of these drugs are now available without prescription, it is especially important that patients be aware of the possibility of an interaction.
  55. 55. Slide 163 Lithium ₊ Calcium channel inhibitors • Case reports of neurotoxicity; no consistent pharmacokinetic interactions. Slide 164 Lithium ₊ Miscellaneous drugs • Succinylcholine, pancuronium – Reports of prolonged neuromuscular blockade. • Metronidazole – Increased lithium concentration. • Methyldopa – Few reports of neurotoxicity. Slide 165 • Sodium bicarbonate – Increased renal lithium clearance. • Iodides – Additive antithyroid effects. • Propranolol – Used for lithium tremor. Possible slight increase in lithium concentration.
  56. 56. Slide 166 Lithium ₊ Antipsychotics CASE REPORTS OF ENCEPHALOPATHY • Lithium and antipsychotic drugs have been used together safety and effectively for years; • however, concern has been expressed that the combination may cause an encephalopathy in certain persons. • Although the interaction has been reported most frequently with haloperidol (Haldol), a number of other antipsychotic drugs have also been implicated. • A clear cause-and-effect relationship has not been established;nonetheless, caution is advised, and the simultaneous use of high doses of the two drugs should be avoided Slide 167 Slide 168 OTHE EFFECTS • worsening of extrapyramidal adverse effects, and neuroleptic malignant syndrome. • Inconsistent reports of altered red blood cell and plasma concentrations of lithium, antipsychotic drug, or both. • With quetiapine can cause somnolence, but is otherwise well tolerated • With ziprasidone – may modestly increase tremor Lithium ₊ Anticonvulsants • combinations helpful for treatment resistance • When two drugs are used together,. In addition, lithium offers some protection against carbamazepine-induced granulocytopenia, although whether it does the same for the rare agranulocytosis and aplastic anemia is unknown
  57. 57. Slide 169 • No significant pharmacokinetic interactions. NEUROTOXICITY • Occasional reports of; but are usually avoidable with careful clinical management • CBZ can cause hyponatremia, which in turn lead to lithium retention and toxicity SHARED ADVERSE EFFECTS • may be more pronounced; for example, tremor and weight gain from lithium and divalproex Slide 170 Lithium ₊ Antidepressants • In general, lithium and antidepressant combinations are safe and effective, although there have been occasional reports of a serotonin-like syndrome when lithium was combined with potent SSRIs. • Serum lithium concentrations are not altered in any substantial way by antidepressant drugs. Slide 171 Lithium ₊ ECT • Concern has been expressed that the presence of lithium during ECT increases the risk and severity of cognitive dysfunction, but whether this is true remains controversial. • SOP 10th -- a person taking lithium who is about to undergo ECT should discontinue taking lithium 2 days before beginning ECT to reduce the risk of delirium
  58. 58. Slide 172 Slide 173 Slide 174 • Sample material • Method of sample collection • Types of tests available • Interpretation of results • Plasma lithium levels Sample Material • Lithium has been measured in virtually every body fluid • but only blood (serum or plasma) is used in clinical practice – Despite considerable research, red blood cell, saliva, and tear lithium measurements and ratios such as red blood cell to plasma have failed to gain widespread acceptance.
  59. 59. Slide 175 Method of Sample Collection THE 12-HOUR INTERVAL SAMPLE • the blood should be drawn in the morning, 12 hours (± 30 minutes) after the last dose • a multiple-dose regimen should be used • a steady-state condition should exist after 5 days (skipped or extra doses within 4 or 5 days should be avoided). Slide 176 • 12-hour serum concentrations will be higher with single as opposed to multiple daily dosing. – The difference may range between 10 and 30 percent and cannot be easily predicted. – Consequently, treatment is usually initiated with at least twice-daily dosing, although switching later to single-daily dosing may have the advantage of improved compliance and fewer adverse effects. Slide 177 Types of Tests Available • Methods used to measure serum lithium include – – – – flame photometry, atomic absorption spectrophotometry, and ion-selective electrode analysis • More recently, colorimetric assays have been developed. One uses finger stick blood and returns a plasma lithium level within minutes. • The analyzers used in clinical laboratories are usually not capable of measuring the low levels of naturally occurring lithium in the blood
  60. 60. Slide 178 Interpretation of Results • it should always be combined with sound clinical judgment. – Clinical toxicity, especially in the elderly, has been well documented within this so-called therapeutic range. – The dose–blood level relationship may vary considerably from patient to patient. • Essential to interpreting serum lithium levels – is knowing the sampling interval (the time between the last dose and the drawing of blood), – the dose form, and the dosage schedule. Slide 179 • the serum level may fluctuate from measurement to measurement, reflecting factors such as – dietary sodium intake, – mood state, – activity level, – body position, – and improper sample collection (use of a lithiumheparin anticoagulant will increase the concentration by more than 1 mEq/L). – Aging of the lithium ion-selective electrode(can cause inaccuracies uptl 0-5 mEq/L) Slide 180 Plasma Lithium Levels The U.S. package inserts • for mania – between 1.0 and 1.5 mEq/L (usually achieved with 1,800 mg of lithium carbonate daily) • and for long-term maintenance – between 0.6 and 1.2 mEq/L (usually achieved with 900 to 1,200 mg of lithium carbonate daily).
  61. 61. Slide 181 MAUDSLEY 10th • Minimum effective plasma level for prophylaxis is 0.4 m mol/L • Optimal range being 0.6—0.75 m mol/ L • Levels above 0.75 m mol / L offer additional protection only against manic symptoms • Optimal plasma range for patients who have unipolar depression is less clear Slide 182 Slide 183 • Pretreatment evaluation • Preparations available • Dosage prediction • Starting dose • Maintenance dose • Discontinuation • Patient education
  62. 62. Slide 184 Pretreatment Evaluation DETERMINED BY • age • associated illnesses • and the presence of other drugs • consequently, a thorough medical history is essential. The history determines the need for and the extent of physical and laboratory evaluations. Slide 185 TESTS TO BE DONE • All patients should have renal(serum creatinine, CUE ) and thyroid(T3,T4,TSH) function tested • A pregnancy test would be appropriate for women of childbearing potential • an ECG in older patients.(maudsley10 th in all patients) • A baseline measurement of weight is also desirable Slide 186 On Treatment Monitoring MAUDSLEY 10TH • Plasma lithium should be checked every 3 months • E GFR and TFTs should be checkded every 6 months • More frequent tests may be • required in those who are prescribed interacing dugs Weignt or BMI should also be monitored ECG repeated annually
  63. 63. Slide 187 Preparations Available IN THE UNITED STATES – immediate release generic lithium carbonate, – slow release (Lithobid and generic lithium carbonate), – controlled release (generic lithium carbonate), – and lithium citrate syrup. ELSEWHERE IN THE WORLD – lithium acetate, – glutamate, – gluconate, – orotate, – and sulphate Slide 188 • There are no parenteral forms. • Both 300 mg of the carbonate and 5 mL of the citrate contain about 8 mEq (mmol) of lithium . • 5.4 m mol/5ml of lithium citrate is equivalent to 200 mg of lithium carbonate • Clinicians should be aware the lithium and lithium carbonate are not interchangeable (300 mg of lithium is equivalent to 1,597 mg of lithium carbonate). Slide 189 Dosage Prediction DIFFERENT TECHNIQUES • giving a single dose of lithium carbonate and using the serum concentration after a given interval (usually 24 hours) to predict the maintenance dose; • measuring renal lithium clearance; • and the use of mathematical models.
  64. 64. Slide 190 • Thus far, prediction techniques have not been widely accepted • and most clinicians continue to adjust the dosage based – on the patient's clinical condition – and previous blood concentrations. Slide 191 Starting Dosage • Initiated in divided doses. – Once a patient is stabilized, single daily dosing is sometimes more convenient. • In general, a conservatively low dose is started, perhaps 300 mg two or three times daily, – a serum concentration is obtained after steady state is reached (in 4 or 5 days), and the dose is adjusted accordingly. Slide 192 • In the presence of normal kidney function – a total daily dose of 1,200 to 1,800 mg of lithium carbonate generally produces an antimanic serum concentration of 0.8 to 1.2 mEq/L. – Maintenance levels of 0.6 to 1 mEq/L can usually be attained with 900 to 1,200 mg daily • Maudsley 10th-start at 400 mg at night(200 mg elderly). Plasma levels after 7 days, then 7 days after every dose change until the desired level is reached
  65. 65. Slide 193 INDIVIDUAL VARIATIONS • Patients vary widely in the dose required to reach a desired blood concentration, • the elderly usually require lesser amounts. • Is best to follow maxim “ treat the patient , not the laboratory results” Slide 194 Slide 195 LOADING THE LITHIUM • to produce a more rapid onset of action • has become more appealing because of economic pressures to minimize the length of hospital stay. Maintenance Dosage • patients must be evaluated clinically • lithium levels determined periodically • and appropriate laboratory tests performed at regular intervals. • Monthly visits are common early in treatment if the clinical course is uncomplicated. Patients who have been stable for extended periods may be seen at intervals of 3, 4, or even 6 months.
  66. 66. Slide 196 Discontinuation • Lithium should be discontinued if it is ineffective or not tolerated. – Patients may stop the drug for other reasons, such as a perceived or real loss in creativity, feeling cured, or a dislike for feeling controlled by a medicine. • After a period of stability with maintenance therapy, a trial off lithium may be considered, – although the risk of recurrence is substantial (especially if there have been several prior episodes), – and there have been reports of failure to respond to lithium when treatment is reinstituted. Slide 197 • Discontinuation should be gradual over many weeks – because more abrupt discontinuation appears to be associated with a higher likelihood of early recurrence, especially of mania. – Maudsley 10 th-reduce slowly over at least 1 month. Avoid intermittent reduction in plasma levels of > o.2 m mol/L • Teaching patients and significant others to recognize early signs of recurrence is an important part of the discontinuation process. Slide 198 Patient Education • plays an important role in ensuring safe, effective, and compliant long-term treatment. • written materials • and support programs, such as those by the Depression and Bipolar Support Alliance (DBSA) (formerly the National Depressive and Manic Depressive Association),
  67. 67. Slide 199 References Maudlsey prescription guidelines 10 th Slide 200