Biologic Therapy
ANTIPSYCHOTICS
These are the “major tranquilizers” that revolutionized psychiatry by providing an effective treatment for large numbers of psychotic patients (1). Their antipsychotic effect is due not to sedation but to a specific action on the thought and mood disorder.
Drugs Available
Many different available antipsychotics are divided into two major categories: (a) for the first 30 years, we have used the traditional antipsychotics, drugs that acted through powerful D2 receptor blockade; and (b) since the early 1990s, we have added the atypical antipsychotics, drugs that affect the D2 receptor to a lesser degree while providing significant blockade of the 5-HT2A receptor (2). Although both types of drugs are effective, the newer medications have several significant advantages that have caused them rapidly to become the “class of choice.” Common examples of both classes are listed in Table 23.1.
TRADITIONAL ANTIPSYCHOTICS
Indications for Use
Recommended for
Acute schizophrenia and other acute psychoses (e.g., amphetamine psychosis, organic psychoses). They should be used in conjunction with lithium in the acute manic attacks of bipolar disorder.
Chronic schizophrenia.
Major depression with significant psychotic features; used in conjunction with an antidepressant.
Tourette syndrome: haloperidol is the drug most commonly used.
TABLE 23.1 ▪ The Antipsychotics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Other uses:
Antipsychotics can be of temporary use in several conditions (e.g., acute agitation of a nonpsychotic nature, antiemesis).
Mechanisms of Action
The dopamine hypothesis postulates that schizophrenia is secondary to increased central dopamine activity. Traditional antipsychotics are thought to act primarily by a broad and powerful postsynaptic blockade of the D2 receptors. The three major CNS dopamine pathways affected by these medications, with their putative activities, are
Nigrostriatal: Extrapyramidal actions
Tuberoinfundibular: Endocrine actions (increased prolactin)
Mesolimbic: Antipsychotic actions (probably)
The different side-effect patterns of the various antipsychotic drugs are thought to be due to their different locations of primary activity. However, traditional antipsychotics also block central noradrenergic (norepinephrine; NE) receptors, thus we cannot be certain whether dopamine (DA) or NE blockage (or another mechanism entirely) is responsible for the antipsychotic effect of these drugs.
Pharmacokinetics
Chlorpromazine (as a classic example) is variably absorbed from the intestine and is probably partly degraded in the mucosal wall. It is approximately 95% protein bound. Much higher blood levels are attained after i.m. or i.v. than p.o. administration. The half-life is 1 to 2+ days, but variable, with the majority of the drug stored in body fat. Marked interindividual differences are found in blood levels (reasons are unclear).
Metabolism is complex (e.g., chlorpromazine is degraded by sulfoxidation, hydroxylation, deamination, and demethylation to form well over 100 metabolites). Some of the metabolites are active, and some are inactive; it is not completely worked out. In part because of this complexity, measured plasma levels of many antipsychotics are not clinically useful. In contrast, certain other antipsychotics (e.g., haloperidol, thiothixene) have a simple metabolism; however, their plasma measurement as a guide to outcome is of uncertain value.
Side Effects
Side effects are common and are almost unavoidable at higher drug dosages. Fewer side-effect problems is a major reasons for the superiority of the newer antipsychotics. The particular pattern of
side effects is in part determined by the chemical class of any given antipsychotic. These side effects also have marked interindividual variability. The most common side effects (Table 23.2) of these medications include sedation, extrapyramidal and anticholinergic symptoms, hypotension, weight gain, and reduced libido, but many other side effects occur as well.
side effects is in part determined by the chemical class of any given antipsychotic. These side effects also have marked interindividual variability. The most common side effects (Table 23.2) of these medications include sedation, extrapyramidal and anticholinergic symptoms, hypotension, weight gain, and reduced libido, but many other side effects occur as well.
TABLE 23.2 ▪ Most Common Side Effects of the Traditional Antipsychotics | |||||||||||||||||||||||||||||||||||||
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Sedation: Common; use a qd schedule, if possible.
Anticholinergic symptoms:
Dry mouth: Common. May lead to moniliasis, parotitis, and an increase in cavities. Consider treatment with oral water and ice, sugarless gum; also neostigmine, 7.5 to 15 mg p.o.; pilocarpine, 2.5 mg p.o. q.i.d.; or bethanechol, 75 mg daily.
Constipation: Treat with stool softeners.
Blurred vision: Near vision. Treat with physostigmine drops, 0.25% solution, 1 drop q6h, if it is a major problem.
Urinary hesitancy and retention: Consider using urecholine, 10 to 25 mg p.o. t.i.d.
Exacerbation of glaucoma
Central anticholinergic syndrome: Occurs particularly in those patients simultaneously taking several drugs with anticholinergic properties [e.g., an overdose (OD) or a patient taking an antipsychotic, an antidepressant, and an antiparkinsonian]. The syndrome can vary from mild anxiety and vasodilatation to a toxic delirium or even coma. It is much more common in the elderly. Symptoms and signs to be looked for include:
Anxiety, restlessness, agitation—grading into confusion, incoherence, disorientation, memory impairment, visual and auditory hallucinations—grading into seizures, stupor, and coma.
Warm and dry skin, flushed face, dry mouth, hyperpyrexia.
Blurred vision, dilated pupils.
Absent bowel sounds.
Treat an acute delirium with withdrawal of the causative agent, close medical supervision (e.g., cardiac monitor), and physostigmine, 1 to 2 mg i.m. or slowly i.v. (e.g., 1 mg/min). Repeat in 15 to 30 minutes and then every 1 to 2 hours, if needed. Avoid physostigmine in patients with bowel or bladder obstruction, peptic ulcer, asthma, glaucoma, heart disease, diabetes, or hypothyroidism. Watch for cholinergic overdose (salivation, sweating, etc.), and treat with atropine (0.5 mg for each milligram of physostigmine).
Extrapyramidal symptoms: These reactions are common, get worse with stress, disappear during sleep, and wax and wane over time.
Acute dystonic reaction: An involuntary sustained contraction of a skeletal muscle that usually appears suddenly (over 5 to 60 minutes). The jaw muscles are most frequently involved (i.e., “lock-jaw”), but other muscle systems may also be disturbed (e.g., torticollis, carpopedal spasm, oculogyric crisis, even opisthotonos). Usually occurs during the first 2 days of treatment (in 2% to 10% of patients, more common in younger patients).
Parkinson-like syndrome: The three primary symptoms occur individually or together, usually during weeks 1 to 4 of treatment. They are more common in older patients.
“Tremor”: An irregular tremor of the upper extremities, tongue, and jaw. It occurs with both movement and rest and is slower than the tremors produced by tricyclic antidepressants (TCAs) and lithium.
“Rigidity”: A cogwheel rigidity that starts with the shoulders and spreads to the upper extremities and then throughout the body.
“Akinesia”: A “zombie-like” effect with slowness, fatigue, micrographia, and little facial expression. It may occur alone and at any time during the course of treatment and is easily mistaken for social withdrawal or depression.
Akathisia: Common. Patients are fidgety, constantly move their hands and feet, rock from the waist, and shift from foot to foot. Easily mistaken for anxiety or agitation. The patients are typically dysphoric. Treat with anticholinergics, propranolol (10 mg t.i.d., 30 to 120 mg/day), or lorazepam.
Rabbit syndrome: Involuntary chewing movements.
Tardive dyskinesia: Slow choreiform or tic-like movements, usually of the tongue and facial muscles, but occasionally of the upper extremities or the whole body. Risk is increased in the aged, those with organic brain syndrome (OBS), females, high doses of medication, simultaneous use of several antipsychotics, and possibly long duration of treatment. Develops over months or years of antipsychotic use; a few severe cases may be irreversible, but it usually follows a stable, benign, long-term course. Symptoms disappear with an increased dosage of antipsychotic: do not “misread” the movements as a worsening psychosis, raise the dose of medication, remove the symptom, and thus begin a vicious cycle. “Drug holidays” do not seem to prevent, and may even worsen, the development of TD. No acceptable treatment is known. Try to discontinue the antipsychotic, if possible.
Treatment of Extrapyramidal Symptoms
Treat with the anticholinergic antiparkinsonism drugs (Table 23.3):
TABLE 23.3 ▪ Antiparkinsonism Drugs | ||||||||||||||
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Begin at a lower dosage and increase over a several-day period. Use for several weeks, and then discontinue if possible. Try not to use for more than 2 to 3 months (although they may be necessary over the long term in a few patients). They probably should not be used prophylactically (begun when antipsychotics are started), except in those patients very likely to be resistant to taking medications. Treat acute dystonic reactions immediately (i.m. or i.v.) with (for example) benztropine (Cogentin), 1 mg; diphenhydramine (Benadryl), 25 to 50 mg; or diazepam (Valium), 5 to 10 mg; and then begin regular oral dose for several weeks. These drugs often worsen side effects of TD; they may also be abused.
α-Adrenergic blocking symptoms: Orthostatic hypotension, inhibition of ejaculation (particularly thioridazine).
Cholestatic jaundice: Probably a sensitivity reaction. Fever and eosinophilia, usually during the first 2 months of treatment
(in 1% of patients taking chlorpromazine). Little crosssensitivity with other antipsychotics.
Agranulocytosis: Usually in elderly women during the first 4 months of treatment but can occur any time. Train patients to report persistent sore throats, infections, or fever. Rare.
Neuroleptic malignant syndrome (NMS): Rapidly developing (hours to 1 to 2 days) muscular rigidity and cogwheeling, fever, confusion, hypertension, sweating, tachycardia. Look for rhabdomyolysis with myoglobinemia and very elevated CPK. In 1%+ of pts, particularly (but not exclusively) after high-dose, high-potency depot medications, but not strongly dose related. Often fatal if untreated. Stop medications immediately; provide medical support; “possibly” helpful are dantrolene (muscle relaxant; blocks intracellular Ca2+ release; 400 mg/day) and bromocriptine (dopamine agonist; 7.5 to 45 mg/day, t.i.d.). Patient may recover over a 5- to 15-day period. It typically does not recur on later reexposure to antipsychotics.
Hypothermia; hyperthermia: Watch out for hot seclusion rooms.
Weight gain, obesity.
Pigmentary changes in skin: Particularly with chlorpromazine. A tan, gray, or blue color.
Retinitis pigmentosa: Possible blindness. Occurs with dosages of thioridazine greater than 800 mg/day.
Photosensitivity: Bad sunburns with chlorpromazine (Thorazine).
Grand mal seizures: Particularly with rapid increases in dose.
Nonspecific skin rashes: In 5%.
Reduced libido in men and women.
Increased prolactin levels: Produces galactorrhea, amenorrhea, and lactation.
ECG changes: Particularly with thioridazine: T-wave inversions, occasionally arrhythmias.
Appears safe during pregnancy: no known congenital abnormalities. Slight hypertonicity among newborns, but little effect on a nursing infant.
Suicide is difficult but possible with the antipsychotics; it requires very large doses.
Drug Interactions
Antacids: May inhibit absorption of oral antipsychotics.
Tricyclic and selective serotonin reuptake inhibitors (SSRI) antidepressants: May inhibit antipsychotic metabolism and increase plasma levels, and vice versa.
Treatment Principles
Drug choice: The primary reason to choose one drug over another is the side-effect spectrum. They are all equally capable of controlling psychosis when used appropriately. If a patient or a similarly affected family member has responded well to one medication, try it. If a patient has a seizure disorder, use a high potency drug (e.g., fluphenazine, haloperidol).
Treatment of acute psychosis: Sedating antipsychotics that can be given i.m. usually provide the best control initially (e.g., haloperidol, chlorpromazine), although they have no long-term advantages. Give orally if the patient is cooperative, but i.m. if he or she is not.
If possible, give a small test dose (e.g., haloperidol, 5 mg) and wait 1 hour to see if it is tolerated.
Then begin haloperidol, 10 to 15 mg/day; chlorpromazine, 300 to 400 mg/day; or the equivalent. Use t.i.d. or q.i.d. schedule initially, and then switch to b.i.d. or qd after 1 to 2 weeks. A HS schedule is usually well tolerated and helps insomnia. It may be necessary to increase to 500 mg/day of chlorpromazine, 15 to 20 mg/day of haloperidol, or the equivalent. Rarely go higher. If side effects become a problem, begin antiparkinsonism drugs or reduce the dosage and increase more slowly, or both.
If the patient is wild and needs immediate control and effective physical control is not readily available, consider more rapid tranquilization [e.g., haloperidol, 5 mg i.m. every hour ×3 to 4 (or, perhaps more effective, haloperidol, 5 mg + lorazepam, 2 to 4 mg, i.m., in the same syringe)]. Monitor carefully for hypotension or oversedation. Once the patient is under control, switch to the preceding daily schedule.
Disease control is cognitive as well as behavioral: The goal is not just to “quiet” the patient. Improvement is slow and often partial. Increasing socialization is an early sign of a drug response. Agitated, disruptive behavior usually improves in the first several days. The thought disorder disappears over weeks or months. Traditional antipsychotics improve the positive symptoms of psychosis (e.g., hallucinations, delusions, bizarre behavior), but, unfortunately, they usually do not change the negative symptoms (e.g., flat affect, social impairment)—a major problem (addition of a low-dose SSRI occasionally helps). Patients who are “acutely crazy” are most likely to respond well, as are those with good premorbid functioning who are having their first psychotic episode. If significant obsessive-compulsive symptoms are present, consider a trial of clomipramine. If a
depression appears, consider switching to an atypical antipsychotic: antidepressants are of modest help at best.
If a patient does not respond, switch to another drug of a different type. However, the unimproved patient needs at least one 2- to 3-week trial at a higher dose of an antipsychotic before you conclude that he does not respond to medication. Rarely is there any reason to use two different antipsychotics simultaneously. The most common cause for lack of response is underdosage (and noncompliance), but always be wary that the patient may have an organic psychosis.
Once improvement has occurred, maintain drug levels over a 1- to 2-month period and then consider reducing to maintenance levels. If this is the first episode of an acute psychosis in a previously well-functioning patient, consider discontinuing the medication in 6 months to 1 year. If this episode is one of many, the patient may need maintenance medication for years.
Antipsychotic maintenance therapy: Decrease dosage slowly (over weeks to months) to one third or one fourth of the immediate dose. If a relapse begins, increase the dose. About 90% of patients relapse (during first 24 months) without medications; 40%+ relapse while taking them. Teach the patient to recognize his or her own developing relapse so it can be caught early.
Traditional antipsychotics are often unpleasant to take, so compliance is a major problem with outpatients (particularly those patients who are suspicious and paranoid). Pay attention to and work aggressively to control side effects (particularly akathisia). If the patient is reluctant to take daily medication, consider the long-acting depot forms of two very potent antipsychotics: fluphenazine decanoate and haloperidol decanoate. They can be given i.m. every 2 to 4 weeks in very low doses [e.g., fluphenazine decanoate (12.5 to 25 mg i.m. every 2 weeks) or haloperidol decanoate (50 to 100+ mg i.m. every month)]. The relapse rate may be slightly increased at these doses, but side effects and compliance usually are improved. (Depot medications may be preferable, whether or not the patient is noncompliant, particularly in the medication-refractory patient.)
ATYPICAL ANTIPSYCHOTICS
Currently six new antipsychotics are available in the United States. Five of the six quickly have become the initial treatment of choice for schizophrenia and other psychotic conditions. Choose one of them first because
They have many fewer side effects than the traditional antipsychotics in low to moderate doses. Thus compliance is likely to be much improved. However, they do produce weight gain, hyperglycemia, and perhaps diabetes.
They are at least equally effective in treating the positive symptoms of schizophrenia and all “may” have greater effectiveness at treating the negative symptoms as well.
They may produce less cognitive impairment than the traditional medications.
They seem to allow the patient a higher quality of life than the traditional antipsychotics, and they improve mood.
With the exception of clozapine, they appear quite safe.
Early studies have found them to have a comparatively low relapse rate.
Although these medications seem to be a marked improvement over earlier antipsychotics, questions are being raised [e.g., the CATIE study (3)]. With the exception of clozapine, they appear to be no more effective than the traditional antipsychotics, although more free from side effects. However, it does appear that they all work through some variation of the same mechanism: they all have a modest to moderate effect at blocking the D1 to D4 receptors and, unlike the older drugs, a moderate ability to block the 5-HT2A receptor, among others. Clozapine, the only one of the six medications that is not a first-line drug (because of an uncommon but very dangerous side effect of agranulocytosis), has been shown fairly clearly to be the drug of choice for treatment-resistant schizophrenia. Suggestive, but less complete and convincing, evidence is available that one or more of the other newer medications also are effective in patients in whom the older antipsychotics have failed (4). Too few comparison studies among these medications have been done to allow the clinician to decide which one is preferable for which patient. They all seem to be roughly equivalent. They currently also are being used fairly widely (and successfully) in conditions like bipolar disorder (mania), intermittent explosive disorder, and in geriatric patients with agitated behavior or dementia or both. The limits of their utility has not yet been reached. One negative feature (at this time) to these medications is that they all are quite expensive. Also, they may, as a group, require 2 to 3 weeks before significant improvement is seen. Finally, they have a “black box” warning for increased mortality when used in elderly patients with dementia-related psychosis.
Most of the general principles followed when treating patients with the older medications also apply here. For example, (a) a complete trial takes about 8 weeks, (b) a patient who
smokes heavily generally requires a higher dose of medication because of increased clearance, and (c) if a patient is prone to relapse when taken off medication, any one of these drugs appears to be an appropriate choice for a maintenance regimen.
smokes heavily generally requires a higher dose of medication because of increased clearance, and (c) if a patient is prone to relapse when taken off medication, any one of these drugs appears to be an appropriate choice for a maintenance regimen.
Specific New Medications
Clozapine (Clozaril), a unique antipsychotic (modest D2, receptor blockade; strong D4 and 5-HT2a receptor blockade) should be used with schizophrenic patients who cannot tolerate or are refractory to traditional and/or atypical medications (5). Marked improvement occurs in almost 30% of treatment-resistant patients with chronic illness; modest improvement in another 10% to 20%. Unlike other antipsychotics, clozapine may improve symptoms of apathy, withdrawal, anhedonia, and flat affect: a “significant cure” in a few patients. It also has mood-stabilizing properties; consider in schizoaffective, manic (6), and psychotically depressed patients.
After a thorough medical (laboratory) examination, begin dosage at 25 mg and increase to 300 to 400 daily (b.i.d. to t.i.d. schedule) over a 2-to 3-week period. (It is very expensive, although a generic is available.) A response may take weeks or even months. Upper limit is 900 mg/day, but be very cautious above 600 mg, because some side effects are related to dose and speed of increase [e.g., sedation, grand mal (GM) seizures (unusual under 300 mg; 5% of patients over 600 mg; do not use in patients with a history of a seizure disorder)]. Other SEs include sialorrhea, weight gain (and very likely diabetes), tachycardia, hypotension, fever, and elevated liver enzymes. It produces almost no EPS or TD. Its blood level may increase if used with SSRIs (particularly fluvoxamine), and NMS may be a risk, particularly if lithium is used concurrently. Clozapine has a difficult withdrawal, so discontinue slowly.
The life-threatening side effect is agranulocytosis: about 1% of patients; usually during months 1 to 6 (but possible anytime); requires weekly WBC with differential for the first 6 months, then every 2 weeks for 6 months, then monthly indefinitely (stop medications if the WBC is less than 3,000 or granulocytes less than 1,500); not dose related. If WBCs decrease below 2,000, never rechallenge the patient with clozapine. Do not start clozapine unless the WBC count is more than 3,500. Do not use in patients with known blood dyscrasias or who are taking drugs with similar effects on the WBCs (e.g., carbamazepine). TAKE THESE GUIDELINES SERIOUSLY.
Risperidone (Risperdal) was the second new antipsychotic released in the United States. It has fewer side effects than previous antipsychotics, is safe in overdose, and seems to affect both positive and negative symptoms. Begin with 0.5 to 1 mg b.i.d. and increase slowly; the ideal final dose for most patients is 4 to 6 mg/day (usually b.i.d. or qd). It is usually effective and well tolerated at that level, although the risk for EPS, orthostatic hypotension, agitation, and elevated prolactin is real and increases significantly above 6 mg/day. TD has been seen with this medication; weight gain is minor. A long-acting injectable form is available (Risperdal Consta); the usual dose is 25 to 50 mg i.m. q2 weeks.
Olanzapine (Zyprexa) is effective when taken in a once-daily dose of 10 to 20 mg (begin with 5 mg/day), and it is available in an i.m. form for immediate treatment. It seems to produce less EPS than risperidone but produces considerably more weight gain (and diabetes and hyperlipidemia) as well as sedation and postural hypotension. It might be slightly more effective than the other atypicals (except clozapine), but it presents very high metabolic risk if not monitored very closely.
Quetiapine (Seroquel) appears the equal of the other new antipsychotics. Its side effects are similar to those of olanzapine, although perhaps not as severe, but weight gain, sedation, dizziness and orthostatic hypotension may be problems. The range of dosage is broad, with clinically similar patients requiring anywhere from 200 to 800 mg daily (b.i.d. recommended, short half-life).
Ziprasidone (Geodon) seems to be a very effective medication, which has the advantage of very minimal EPS and weight gain (if any at all) and improvement in mood. Its side effects tend to be GI complaints: nausea, abdominal pain, dyspepsia, dizziness and constipation, although they are generally mild. Ziprasidone also has the advantage of being available in pill, liquid, and i.m. form. It appears to be effective for treating acute mania. Finally, it acts as a 5-HT1A agonist and thus may be an effective antianxiety agent as well. Dosage should be 60 to 80 mg, p.o. b.i.d. or 10 mg 1m q 2hr as needed to a maximum of 40 mg.
Aripiprazole (Abilify) possesses most of the characteristics of the atypical antipsychotics and, at a normal dose of 10 to 30 mg/day (once daily), may be particularly free of side effects. It can be too activating for some patients, so begin slowly. The most common side effects include agitation, nausea, akathisia, tremor, and headaches.
MOOD STABILIZERS
Lithium Carbonate
Lithium carbonate (Li+, atomic number 3), is available in slow-release form: Eskalith CR, Lithobid Slow-Release Tablets.
Indications for Use
It is recommended for
“Classic” acute bipolar disorder, manic. Lithium is the drug of choice for stabilization of an acute manic attack (80% of patients normalize) although, because of the usual 7- to 10-day delay in clinical onset, an additional drug may be needed initially for control. Best for “classic” bipolar disorder; for “rapid cyclers,” use anticonvulsants instead (only about one third respond to Li).
Acute depression: bipolar (good; up to 80% respond, but it is slow to act, takes 3 to 6 weeks), and unipolar (about one third respond, thus it is a second-choice drug). Definitely consider the addition of Li to augment a partial response to another (any other) antidepressant; 50% respond (usually quickly, in 1+ weeks).
Long-term prophylaxis of mania in a bipolar patient: It is quite effective at preventing recurrences when coupled with an anticonvulsant. Be careful of chronic renal toxicity.
Possible uses include
Prophylaxis for bipolar disorder, depressed, and for major depression.
May assist (usually) or replace antipsychotics in treatment of a few patients with schizoaffective disorder.
May help control mood swings, impulsive aggression, and explosive outbursts, regardless of cause, and retarded patients with aggressiveness or self-mutilation or both.
Curiously, it is effective in chronic prophylactic treatment of cluster headaches.
Mechanisms of Action
The reasons for the clinical effects are poorly understood, although Li does enhance presynaptic serotonergic neurotransmission, “seems” to reduce pre- and postsynaptic dopamine transmission, and increases plasma NE levels.
Pharmacokinetics
Lithium is quickly absorbed from the GI tract (completely absorbed in 8 hours) and develops a peak plasma level in 1 to 3 hours. It is not protein bound or metabolized and is excreted by the kidney. The cerebrospinal fluid (CSF) concentration is 30% to 60% of that in plasma and equivalent to that in red blood cells (RBCs). It is concentrated by bone and by thyroid (4 to 5 times that in plasma).
Lithium can be used safely only if blood concentrations are monitored carefully (oral dosage is not an adequate measure). To obtain consistent levels, draw blood 12 hours after the last dose (e.g., take evening dose, then draw before breakfast). The lithium half-life is 18 to 36 hours (fastest in youth, slowest in elderly); a constant oral dosage requires 5 to 8 days to reach steady state. Once a steady state is reached, the lithium level is proportional to the daily oral dose (and determined by the renal clearance).
Side Effects
The number and severity of side effects increase with elevated or rapidly changing/increasing Li blood levels. A slight change in blood level (0.1 to 0.2 mEq/L) may alter dramatically the number or intensity of the side effects. Minor side effects (tremor, impaired coordination, dysarthria, thirst, anorexia, and GI distress) commonly occur at therapeutic levels (0.8 to 1.5 mEq/L), and serious effects (nausea and vomiting, slurred speech, diarrhea, coarse tremors, severe ataxia, confusion, delirium, seizures, coma, death) may occur at only slightly higher levels (e.g., as low as 2.0 to 2.5 mEq/L but more commonly at 3 to 5 mEq/L). Some evidence suggests that mild side effects can be controlled with a daily dietary supplement of 20 to 40 mEq of K+. Lithium has a very narrow margin of safety and is a dangerous drug in overdosage. It should be given cautiously (or not given at all) in patients who are dehydrated, febrile, have sodium depletion (kidney reabsorbs more lithium), or have major renal or cardiovascular disease. Brain-damaged patients and the elderly are at risk for side effects even at low blood levels: use with care.
Normal subjects administered lithium report irritability and emotional lability, anxiety, mild depression, tiredness and malaise, weakness, inability to concentrate, impaired memory, and slowed reaction time. Patients taking lithium often experience a “lithium-induced dysphoria”; 25% to 50% stop lithium against medical advice (AMA). Unlike other psychoactive medication, sedation is not a side effect.
▪ Neurologic
EEG: Usually shows increased amplitude and generalized slowing (in 50% of patients at therapeutic blood levels).
Headaches, occasional slurred speech.
Toxicity: confusion, poor concentration, and clouding of consciousness; leads to delirium; leads to coma; leads to death.
Cerebellar effects: dysarthria, ataxia, nystagmus, severe incoordination.
Basal ganglia effects: Parkinsonian symptoms, choreiform movements.
Seizures: grand mal; status epilepticus.
▪ Neuromuscular
Hand tremor (fine, fast) that does not respond to anticholinergics. Occurs in 50% of the patients started on lithium, but the incidence decreases with time (5% of long-term patients).
Treat with β-blockers (e.g., propranolol, p.o., 30 to 80 mg/day.
Muscular weakness: one third of patients during the first week of treatment; transient.
Neuromuscular toxicity: hyperactive reflexes, fasciculations, paralysis.
▪ Kidney
Polyuria and polydipsia: secondary to a vasopressin-resistant, diabetes insipidus-like syndrome. Reversible and occurs in 50% of all new patients (5% of all with chronic disease).
Reversible oliguric renal failure with acute lithium intoxication.
Possible irreversible nephrotoxic effect in a few with chronic disease: focal interstitial cortical fibrosis with tubular atrophy and sclerotic glomeruli. Look for a gradually increasing blood lithium in patients taking a constant oral dose. Increased serum creatinine and an increased 24-hour urine volume are found. Poorly characterized currently, this serious effect of prolonged lithium administration may limit the ability to use lithium prophylactically in some.
▪ Blood
Leukocytosis (10,000 to 14,000 WBCs: neutrophilia with lymphocytopenia). Common and reversible, it is persistent but periodic while the patient is taking lithium.
Occasional increased erythrocyte sedimentation rate (ESR).
▪ Gastrointestinal
About 30% of patients have GI symptoms in the early weeks of treatment: gastric irritation, nausea, anorexia, diarrhea, bloating, abdominal pain (a switch to lithium citrate may relieve symptoms).
▪ Heart
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