IGSLI: Clinical Effects and Indications

Clinical Effects and Indications

Treatment of Acute Mania with Lithium and Other Pharmaceuticals (H.-P. Volz, H. Sauer)

Abstract

Lithium is the medication of choice for patients suffering from mild to moderate mania. There is as well substantial clinical evidence for recommending valproate or olanzapine monotherapy in mild to moderate cases.
Patients suffering from severe or mixed mania who exhibit pronounced motor restlessness and psychotic symptoms should be treated first with lithium plus an atypical antipsychotic or valproate plus an atypical antipsychotic such as olanzapine or risperidone.
If a patient does not respond to first line treatment, combination of two first-line treatments should be considered. If no improvement is seen, clozapine or electro-convulsive therapy may be indicated.
Lithium is less effective for rapid cycling mood disorder and mixed manic-depressive episodes than it is for classical manic syndromes. For mixed episodes valproate may be preferred over lithium. The therapeutic efficacy of lithium is also lower in the context of organic mania.

Treatment of Acute Depression with Lithium (M. Bauer)

Abstract

The majority of open and controlled studies demonstrate that acute lithium therapy has a clear antidepressive effect, especially among depressive patients with bipolar disorder.
Nevertheless, lithium is widely regarded as a substance with only “moderate antidepressive” efficacy and is not the medication of first choice for the acute treatment of severe depressive illness. This prevailing opinion possibly is related to the narrow therapeutic index of lithium.
However, a number of clinical situations exist in which lithium plays an important role in the acute treatment of depression. These include:

bipolar patients suffering from a depressive episode of mild to moderate severity. (Bipolar disorder is a good predictor of a positive response to lithium, and the risk that a patient will switch to a manic state is lower when he or she is treated with lithium instead of antidepressants.)
depressive patients who do not respond to antidepressant monotherapy. (Lithium “augmentation”: the use of lithium as an adjunct to antidepressant monotherapy has been confirmed as an effective means of treating therapy-resistant depression. Between 50-60% of therapy-resistant depressive patients respond to the addition of lithium within 2-6 weeks.)
patients who switch into mania during treatment with an antidepressant.
unipolar patients in whom lithium prophylaxis is already indicated due to recurrent depressive episodes.
patients who, for medical reasons, should not be given antidepressants.

The Long-term Prophylaxis of Affective Disorders with Lithium (W. Greil, N. Kleindienst)

In the long-term treatment of affective disorders, a distinction is made between maintenance therapy (i.e. the prevention of relapse during a period of illness that is not yet completely resolved) and long-term prophylaxis (i.e. the prevention of future recurrences/episodes of illness). For maintenance therapy, the medication administered during the current acute phase of the manic and/or depressive episode is continued for a period of 4-6 months. For long-term prophylaxis, mood stabilizing substances – primarily lithium and antidepressants, but more recently also anticonvulsants – are used.
Long-term prophylaxis is indicated in cases in which a high frequency of recurrences is to be expected. For example, patients suffering from bipolar affective disorders (with manic and depressive phases) experience recurrences more frequently than patients with unipolar depression (with exclusively depressive phases). The recurrence rate also increases with the number and frequency of previous periods of illness.
Controlled studies comparing long-term lithium treatment to placebo (or to no pharmacotherapy) have yielded conclusive evidence that lithium is effective in preventing relapse of bipolar manic episodes, and strong evidence that lithium can prevent relapse of bipolar depressive episodes. There is also sufficient evidence that long-term lithium therapy can prevent the recurrence of unipolar depressive episodes.
Studies comparing lithium to tricyclic and tetracyclic antidepressants in the long-term prophylactic treatment of unipolar depressive episodes have yielded contradictory results: Most studies show the efficacy of lithium to be the same or greater than that of the tricyclics and tetracyclics. In one study, however, lithium was shown to be less effective. In the context of bipolar disorders, there is not yet enough evidence to determine whether anticonvulsants have the same long-term prophylactic efficacy as lithium.
Studies conducted in special lithium clinics and with adequate treatment monitoring have shown that, when the course of disease before lithium treatment was compared to the time during treatment, between 65% and 80% of patients showed a positive response to therapy. Response to therapy was defined as the absence of relapse (i.e. full response) or the decrease in frequency, severity and/or length of recurrent episodes (i.e. partial response). Treatment failure (i.e. non-response) occurred in 20-35% of patients. Naturalistic studies have shown, however, that the effectiveness of lithium in the prevention of recurrent episodes is lower under routine conditions. “Effectiveness” must not be confused with “efficacy” in this context.

Prophylaxis of Schizoaffective Psychoses (G. Lenz, B. Bankier)

Abstract

The introduction of the ICD-10 and DSM IV into clinical practice has made the diagnosis of schizoaffective disorders more reliable and valid.
The scientific evidence for prophylactic efficacy of various compounds commonly used in psychiatric practice is poor. The data encourage the use of lithium and carbamazepine in primarily affective patients, and of clozapine in primarily schizophrenic patients and possibly in mainly affective patients as well.
Studies have shown that patients suffering from the schizomanic/affective subtype (according to RDC) respond well to lithium prophylaxis, whereas those with the schizodepressive/schizophrenic subtype do not.
Among patients with the schizomanic subtype (according to RDC), carbamazepine prophylaxis is just as effective as prophylactic lithium therapy. However, some studies show that among patients suffering from the schizodepressive subtype, carbamazepine is clearly superior to lithium in terms of hospitalization and shows a tendency in terms of fewer recurrences.
In the long-term treatment of patients with the schizophrenic subtype (according to RDC), neuroleptics have been shown to be markedly superior to lithium prophylaxis.

Some open studies indicate that valproic acid may also be able to reduce the frequency and intensity of further schizoaffective episodes.

Selection Criteria for Curative and Prophylactic Lithium Treatment (P. Grof)

When deciding whether a patient will benefit from long-term lithium therapy, it is important to assess the risk of relapse, the psychosocial effects of the disease on the patient, and the general medical risk of lithium treatment.
The recurrence increases with the number and frequency of previous episodes. Although it is possible to accurately predict the course of disease for large groups of patients, doing so for individual patients is difficult due to interindividual variation. In general, the risk of relapse increases with the frequency and number of previous episodes of illness. The risk of relapse is considered high in the following cases: bipolar disease with 2 phases in the previous 4 years, or a total of 3 phases regardless of the time period in which they occur and (b) unipolar disease with 2 phases in the previous 5 years, or a total of 4 phases regardless of the time period in which they occur.
It is important to distinguish between long-term therapy of choice and a limited therapeutic trial. In typical cases of bipolar or unipolar affective disorder, lithium is the long-term therapy of choice when patients experience periods of complete remission and are free of all psychopathological symptoms (i.e. patients with a normal profile according to the MMPI [Minnesota Multiphasic Personality Inventory]).
A family history of bipolar affective disorder increases the chance of a positive response to lithium prophylaxis. However, the occurrence of 4 or more phases in one year decreases, but does not preclude, the chance of a positive response. Lithium therapy can also prevent recurrences in patients suffering from schizoaffective illness or schizophrenia with a periodic course. However, there are no known predictors for these latter two patient groups.
Before deciding in favor of long-term lithium therapy, it is essential to consider carefully the pros and cons of lithium treatment when compared to the other drug regimens currently available.
Manic patients who respond well to acute treatment with lithium are generally those who are suffering from classic manic symptoms. Lithium can be regarded as the therapy of choice in patients who have a history of positive response to acute or prophylactic lithium treatment.

The Differential Effects of Lithium and Their Significance When Terminating Long-term Lithium Therapy (P. Grof)

There is conflicting information in the literature on the consequences of terminating lithium therapy. This is primarily due to the fact that the risk assessments made so far have not taken into account interindividual variation in the effects of lithium treatment.
Lithium therapy can be terminated immediately and need not be tapered off in patients who have responded very well to lithium prophylaxis and have been completely free of symptoms while on treatment. When recurrences do occur, they tend to develop gradually and over a period of time that can range anywhere from several weeks to several years (i.e. according to the natural course of illness before lithium therapy was first initiated). Usually, patients who experience a recurrence can be stabilized again by reinitiating treatment.
If lithium therapy was initiated primarily because of its antipsychotic effects (i.e. unspecifically), abrupt withdrawal can very quickly lead to a recurrence, most often in the form of a “rebound.” Reinitiation of lithium therapy does not always result in restabilization. In such cases, the dosage of lithium should be reduced gradually.
Patients often interrupt or terminate lithium therapy without consulting their physician. Frequently, this occurs at a point in time when the risk of recurrence is particularly high.
Medical reasons for stopping lithium therapy include non-response to the drug, signs of toxicity and severe side-effects. Lithium treatment should also be terminated prior to certain medical examinations and before pregnancy. However, each patient needs to be examined carefully and advised of the potential risks involved in his or her particular case before the decision to terminate lithium treatment can be made.

The Anti-suicidal and Mortality-lowering Effects of Lithium (B. Ahrens, B. Müller-Oerlinghausen)

Abstract

Among patients with affective disorders the risk of suicide is anywhere from 20 to 30 times greater – and overall mortality is 2 to 3 times higher – than in the general population.
Lithium has a mortality-lowering effect, as well as specific anti-suicidal properties. The latter are at least partially independent of the episode-preventing effects of lithium in recurrent depressive and bipolar disorder.
When determining the appropriateness of lithium treatment, it is important to consider any history of suicidal behavior in the patient or the patient’s family.
Patients with a history of suicidal behavior can benefit from the anti-suicidal properties of lithium, even if lithium prophylaxis fails to prevent recurrences. In such cases, it is possible to continue lithium as an adjunct to an alternative prophylactic regimen.
The use of lithium prophylaxis prevents an estimated 200 suicides per year in Germany, despite the fact that the prescription rate of lithium is very low (approximately 0.06% of the population) and, by some estimates, should actually be at least ten times greater.
A mortality reducing effect has not been shown convincingly for any other mood stabilizing or antidepressant drug.

Lithium in the Treatment and Prophylaxis of Pathological Aggression (A. Nilsson)

Systematic research on lithium and pathological aggression conducted in a number of different fields (e.g. studies in adult psychiatry, of children and youths with behavioral disorders, of mentally retarded individuals, and of isolated impulse-control disorders among prisoners) have unanimously shown that the serum lithium levels normally reached in the long-term treatment of bipolar disorders can reduce impulsive aggression.
Scientific investigations of aggression are still plagued by a multitude of methodological problems. There is, for example, still no adequate or uniform definition of aggression. Of particular clinical interest is the pathological overreaction with primarily destructive intent.
The majority of studies on aggression have been conducted in closed institutions. This makes it difficult to devise optimal treatment strategies for outpatient medical care.
The clinical significance of lithium for this indication is minimal. This may be attributable to ethical reservations about prescribing medication to control aggressive behavior, or possibly to problems with compliance in this particular patient population.

Lithium Salts in Child and Adolescent Psychiatry (G.H. Moll, A. Rothenberger)

For the treatment of a manic episode in childhood or adolescence, lithium salts – like neuroleptics – are the medication of choice. A combination treatment of lithium with neuroleptics is possible, but requires especially careful monitoring.
If a child or adolescent suffering from unipolar depressive episodes does not respond sufficiently to treatment with antidepressants, adding lithium salts during the depressive episode – to increase the effectiveness of overall therapy – and then continuing lithium treatment as long-term prophylaxis can be beneficial. After approximately 3 years, the need for further treatment should be assessed.
For adolescents, as well as adults, lithium salts are considered to be the medication of choice in the long-term prophylactic treatment of bipolar affective disorders. In contrast to the treatment of these disorders in adults, however, the unique developmental conditions which characterize young adulthood make it advisable to begin treatment in adolescents at an early stage, i.e. already during the first episode. In the event of non-response, carbamazepine can be administered as an alternative treatment.
Lithium salts can lead to improvements in patients with strongly pronounced explosive aggressive behavioral disorders, as well as in those who exhibit impulsive, self-destructive behavior (i.e. auto-aggression). Therapy should take place in an inpatient setting for at least the first 6 to 8 weeks of treatment. As is the case with the above mentioned affective disorders, there is only minimal evidence of benefit when carbamazepine is used in this indication.
If pedagogical approaches and behavioral therapy have been unsuccessful, child and adolescent patients with intellectual deficiency and who exhibit explosive aggressive and/or auto-aggressive, self-destructive behavior may benefit from inpatient treatment with lithium salts.
The recommended dosage and serum levels of lithium salts, as well as side-effects and contraindications, are the same in adolescents as they are in adults. However, lithium therapy is currently not recommended for children under the age of 12, unless it is administered on a strictly inpatient basis.
Even when therapy with lithium salts is clearly indicated in child or adolescent patients, it should nevertheless be regarded as only one component of a larger, comprehensive, and multifaceted treatment plan that takes into account each patient’s symptoms, state of development and function, as well as his or her specific psychosocial circumstances.

Neurological Indications for Lithium Therapy (A. Berghöfer)

The main application of lithium in the field of neurology is as a treatment for chronic cluster headaches.
Lithium is no longer considered for the prophylaxis of migraine headaches due to contradictory evidence regarding its efficacy in this particular context.
The efficacy of lithium in the treatment of other neurological disorders (Meniere’s disease, epilepsy, Huntington’s disease, Parkinson’s disease, tardive dyskinesia, periodic hypersomnia, Gilles de la Tourette's syndrome, spasmodic torticollis, hypokalemic periodic paralysis) has not yet been demonstrated.
In isolated cases, lithium treatment in patients suffering from symptomatic affective psychoses which appeared in the context of a neurological disorder has been reported to be successful.

The Antiviral Effect of Lithium in the Treatment of Herpes Simplex Infections (J.K. Rybakowski)

Under experimental conditions, lithium inhibits the replication of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) at a concentration of 5-30 mmol/l, most likely by interfering with viral DNA synthesis.
Long-term treatment with lithium at doses typical for the prophylaxis of affective disorders can attenuate or even inhibit the reactivation of labial or genital herpes infections, both in patients with affective psychoses and in individuals who do not suffer from a psychiatric illness.
Topical therapy with 8% lithium succinate ointment has been shown to have a positive therapeutic effect on herpes lesions.
The effect of lithium on herpes infections may not only be due to the inhibition of viral DNA synthesis, but also to the stress-reducing, immunomodulatory, and anti-inflammatory properties of the drug.

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