Diseases, Disorders information

Major congenital anomalies are observed in about 3% of all births. Maternal exposure to drugs or environmental chemicals may be responsible for 4-6% of these anomalies, or approximately 1 in 400 liveborn infants.

Whether birth defects occur in a conceptus exposed to a potentially teratogenic agent depends in large part on two factors: 1) gestational timing of the exposure and 2) the genetic makeup of the conceptus and the mother. Morphogenetic stage of the organism’s development is a key factor in susceptibility to a potential teratogen. Exposure to a teratogenic agent during organogenesis may result in a gross defect involving the organ undergoing formation at that time. Conversely, exposure to such an agent during histogenesis may produce finer structural defects within the target organ system. Substantial evidence suggests that, second only to the gestational timing of exposure, the most important variable is difference in the genetically determined activity of the enzymes involved in the metabolism of drugs and chemicals. This difference is termed pharmacogenetic variation. An important determinant of teratogenic potential is mode of exposure. The teratogenic agent may reach the developing embryo or fetus either by direct passage through maternal tissues (eg, ionizing radiation) or by placental transfer (eg, drugs or chemicals).

Drugs and Chemicals

Epidemiologic studies have determined that most drugs commonly used during pregnancy (eg, aspirin, acetaminophen, metronidazole, caffeine, phenothiazines) are not associated with an increased risk of congenital anomalies. However, based on anecdotal evidence, maternal hyper-thermia seems to be associated with congenital anomalies when the fever persists for a protracted period of time (>24 hours) and is high (at least 101 o F). Numerous other agents have been implicated as teratogens, including chemotherapeutic agents. However, approximately 95% of the 200 most frequently prescribed drugs appear safe for use during pregnancy.

Dosing of lithium

Dose-response relationships of lithium and other proposed mood-stabilizing agents have not been investigated extensively. Most studies have considered the daily minimum or trough serum levels of lithium (ca. 12 hrs after the last dose), which were introduced initially to provide protection from overdosing with this agent of very low therapeutic index (only about 3-fold ratio of toxic to therapeutic levels). Levels of about 0.50-1.25 mEq/L cover the therapeutic range; levels below 0.5 mEq/L are less effective, while levels above 1.0 mEq/L probably provide limited additional benefit but increase side effects and are best reserved for acute mania, rapid cycling, or treatment-resistant cases. Tolerability and compliance may be enhanced by long-term use of relatively moderate doses of lithium (providing levels at 0.6–0.8 mEq/L), as is standard in European clinical practice. Based on animal experimentation and limited and inconsistent clinical data, it has been suggested that once or twice daily dosing with ordinary lithium carbonate may reduce renal side effects, particularly polyuria and nocturia, and increase compliance; however, in view of the narrow margin of safety of his agent, and the risk of CNS intoxication with high peak plasma concentrations (which can be at least 2-3x trough levels), especially in elderly patients, and the limited risk of significant, irreversible, nephrotoxicity of lithium, as well as trivial average reductions in 24-hour urine volumes, once-daily dosing is not recommended as a routine practice. Sustained-release lithium carbonate may limit CNS intoxication risks but can increase GI distress. Many patients are now reluctant to accept lithium treatment owing to popular views of its alleged toxicity or lack of efficacy, as well as issues of stigmatization and denial of illness. Moreover, adherence to long-term lithium treatment is often variable, and requires constant encouragement in order to maximize protective benefits.
Antidepressants
Adverse effects of lithium

Adverse effects of lithium include frequent initial polyuria and thirst and 10%-20% risk of later persistent (but usually reversible), clinically significant diabetes insipidus, associated with elevated circulating levels of antidiuretic hormone (ADH) and unresponsiveness to exogenous synthetic antidiuretic peptides (such as desmopressin). High 24-hr urine volumes (5 L) have been associated with elevated risk of histopathological changes in renal biopsies suggestive of chronic granulomatous, nephron-distorting, inflammation. Nevertheless, irreversible azotemic renal failure due to lithium treatment is rare and is sensitively and simply detected by quarterly or semiannual monitoring of serum creatinine concentrations, watching for gradually rising trends rather than any single abnormal value.

Weight-gain and dermatological disorders (severe acne, worsening of psoriasis, mild alopecia) are common reasons for discontinuing lithium. However, subtle neurological or cognitive effects are among leading reasons to resist or discontinue long-term lithium therapy. These include a high risk of mild resting tremor and impaired handwriting (often responsive to reduced dose or use of propranolol), as well as varying degrees of subjective cognitive impairment, mild mental confusion and even low-grade delirium, which can occur even at trough plasma concentrations in a nominally therapeutic range, particularly in elderly or neurologically impaired patients.

Clinical myxedema is unusual during lithium therapy, diffuse, nontoxic, and non-precancerous goiter can occur, sometimes with a lowering of serum thyroid hormone indices into the low-normal or subnormal range, with elevated TSH as an early harbinger; some clinicians believe that adding supplemental thyroid hormone not only can reduce goiter, but may also contribute to minimizing depression and slowing rapid cycling.

There probably is moderately increased risk of major cardiovascular malformations during the first trimester of pregnancy during lithium use (most commonly, Ebstein’s tricuspid/septal malformations, at 2-5 times above the spontaneous base rate of ca. 1/20,000 live births). Lithium can also induce hypotonia in the newborn, and elimination and tolerance of lithium typically decrease sharply soon after delivery. These risks have strongly encouraged avoiding pregnancy during lithium treatment. Nevertheless, recurrence risks in pregnancy, and especially the neonatal period, are high when lithium is discontinued early in pregnancy (similar to that in nonpregnant women), and particularly rapidly. Sudden discontinuation of lithium (eg, due to pregnancy or other medical contraindications), even in patients who have been euthymic for several years, carries a high risk of early relapse which can be minimized by slowly tapered dosing (over at least one month). While mood-stabilizing anticonvulsants can not be considered safe during pregnancy (mainly owing to spina bifida in >1/100 cases), cautious use of neuroleptics or antidepressants in low-effective doses can be considered when necessary, and ECT is safe and effective in mania or depression during pregnancy. For some high-risk patients, lithium is being used in middle or late pregnancy and the neonatal period to avoid potentially dangerous and life-threatening (suicide, infanticide) recurrences of manic-depressive illness (as many cases of “post-partum psychosis” probably are).

Efficacy of lithium salts

Lithium salts (carbonate or citrate) are relatively specific for the treatment of mania but their onset of useful action is slow (5-10 days). For this reason, and due to the limited margin of safety (therapeutic index) of lithium in acutely disturbed, poorly cooperative, and metabolically compromised patients, many are not treated immediately or primarily with lithium in acute mania. Instead, they are treated temporarily with an antipsychotic agent (often more dramatically effective in mania than in schizophrenia) or a sedative (usually a high-potency benzodiazepine, such as lorazepam [Ativan] or clonazepam [Klonopin]). Lithium salts can then be added safely in gradually increasing doses. Short-term effectiveness in mania is best established in young adults (in whom placebo response rates are surprisingly high: 30%-40%), almost certainly extends to adolescents, is poorly studied in children, and may be less effective and is less well tolerated in the elderly. Lithium is particularly useful for continuation treatment in the months following clinical recovery from an acute episode of mania, and for long-term maintenance treatment aimed at minimizing risk or severity of future recurrences of mania or bipolar depression in cases with severe or multiple episodes. In maintenance treatment, lithium appears to be more effective against hypomanic > manic > depressive phases in bipolar disorder; it is very effective in Type II bipolar disorder (episodic major depression with hypomania or cyclothymia). Lithium probably is also effective adjunctively in nonbipolar depression, including cases of apparent antidepressant unresponsiveness or tolerance (best tested with TCAs), and as an adjunct in recurring major depression, although the place of routine lithium treatment in nonbipolar major depression is less secure and not currently included in FDA-approved guidelines. Poor response to lithium can be anticipated in patients who present with mixed, agitated, or psychotic bipolar states; those presenting depression before mania may do less well than those who present with mania first (D-M-I vs. M-D-I syndrome, in which I = euthymic interval), but rapid-cycling (>4 episodes in any year), and prolonged latency from illness onset to the start of treatment do not necessarily predict a poor response to lithium.

Evidence for efficacy of lithium in acute nonbipolar depression is much weaker than for bipolar depression. Some beneficial effects of lithium in depression may be due to underdiagnosis of bipolar disorder and related conditions, or the possibility that some cases of apparent nonbipolar depression may be phenotypic variants of bipolar disorder (”pseudounipolar” depression hypothesis). It is also very likely that recurring depressive illness can be worsened with excessive antidepressant treatment (rapid cycling, agitation, mixed states, mania or psychosis); such cases may include apparently “treatment-resistant” depression, and less aggressive antidepressant treatment or adding lithium may be useful in their management. Lithium salts (and antimanic anticonvulsants) also may have a place in some other conditions, including cases of secondary bipolar disorder associated with neurological disorders (particularly in the elderly), as well as episodes of aggressive outbursts, even in persons without clear evidence of a primary mood disorder. Other potential medical applications of lithium, as in hyperthyroidism and leukopenia, lacks substantial support.

Surprisingly, lithium is the only form of maintenance treatment in recurring major affective disorders with substantial evidence of reduced suicidal risk (including anticonvulsants, antidepressants, ECT, and psychotherapy, but perhaps not clozapine which has reduced suicide risk in schizophrenia, at least). Recent direct comparisons of lithium with TCA maintenance in unipolar depression and carbamazepine in bipolar cases found more protection against suicide attempts with lithium. It is not clear whether this is a specific effect or a reflection of long-term protection against depression by lithium. Suicide risk is at least six-fold lower on lithium, and may increase over time-on-treatment. Stopping lithium is followed by sharply increased, largely time-limited, risks of recurrences of mania and depression and also suicide attempts and deaths, with evidence that slow discontinuation can reduce this risk. Mortality rates are further elevated in bipolar disorders due to comorbid medical disorders (particularly stress-related cardiovascular and pulmonary diseases) and complications of substance abuse, and treatment may reduce overall mortality risk.