Lithium treatment resistance

Optimize the dose of mood stabilizing medication(s) before adding on lithium, lamotrigine, or antidepressant (e.g., bupropion or an SSRI) if psychotic features are present, add on an antipsychotic ECT used for severe or treatment-resistant depressive episodes or for psychosis or catatonia... 

The combination of carbamazepine with lithium, valproate, and antipsychotics is often used for manic episodes in treatment-resistant patients. 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or an atypical antipsychotic (e.g., risperidone). Risperidone has been shown to be effective in combination with fluvoxamine, paroxetine, or citalopram in treatment-resistant depression. Olanzapine and fluoxetine have been found to be safe and effective in treatment-resistant depression. 

Unfortunately, none of the SRI-drug combination approaches to treatment-resistant OCD can be viewed as firmly established. In the case of SRI plus lithium or SRI plus buspirone, encouraging open-label reports have been followed up by mostly negative controlled trials. The lack of a mean be-tween-group difference should not completely overshadow the observation... 

Post RM, Chuang D-M Mechanism of action of lithium comparison and contrast with carbamazepine, in Lithium and the Cell Pharmacology and Biochemistry. Edited by Birch NJ. London, Academic Press, 1991, pp 199-241 Post RM, Weiss SRB The neurobiology of treatment-resistant mood disorders, in Psychopharmacology The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995... 

In partially responsive or nonresponsive patients, the first issue is to determine whether an individual is truly treatment-resistant, because many receive nontherapeutic doses and the potential for improvement may not be adequately tested. Thus, in some situations, more aggressive treatment (dose increase, augmentation) may be appropriate, if not precluded by adverse effects. In selected cases, it may also be helpful to monitor plasma levels to ensure that they are in a reasonable range (see Pharmacokinetics/Plasma Levels earlier in this chapter). If a patient continues to demonstrate significant symptoms after a sufficient trial (2 to 3 weeks), alternatives to switching to another antipsychotic may include the addition of lithium, an anticonvulsant, or a second antipsychotic agent. An antidepressant or anxiolytic may also be helpful, especially if affective or anxiety symptoms are prominent. 

Lithium Lithium augmentation of standard antidepressants has been reported to significantly benefit previously treatment-resistant and psychotic depressions, particularly in bipolar patients ( 371, 372). There is substantial case report literature reporting that many patients have benefited when lithium was added to ongoing TCA therapy. Often these results occurred rapidly, sometimes with low doses of lithium. Although the results of controlled trials have not been as dramatic, they still support this approach, which should be seriously considered for treatment-resistant major depression. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Post RM, Kramlinger KG. The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry 1989 46 794-800. 

Lithium may also be used in the depressive phase of a bipolar disorder, alone or to augment other antidepressants, and in combination with VPA or CBZ for more treatment-resistant mania (see also Chapter 7). 

Lithium Plus Thyroid Supplementation. Treatment-resistant and rapid-cycling bipolar patients may have an increased frequency of thyroid dysfunction. Further, some patients suffer from subclinical hypothyroidism and improve with the addition of thyroid supplementation. In this context, several case reports involving this population found that high doses of the thyroid hormone levothyroxine sodium (T ) were clinically beneficial (122,123 and 124). Kusalic (1.25) found that 6 of 10 rapid cyclers had hypothyroidism, based on their thyrotropin-releasing hormone stimulation tests. Further, the average number of mood episodes per year decreased by more than 75% (i.e., from 9.7 to 2.2) after thyroxine was added to the treatment regimen. 

Kramlinger KG, Post RM. Adding lithium carbonate to carbamazepine antimanic efficacy in treatment-resistant mania. Acta Psychiatr Scand 1989 79 378-385. 

Another study of nine treatment-resistant patients (despite vigorous treatment with clomipramine plus lithium) found that three patients responded to the addition of trazodone, relapsed when trazodone was discontinued, and responded again when it was readministered (231). A small, double-blind study comparing trazodone with placebo in 21 patients, however, found no difference in therapeutic benefit between this agent and placebo ( 232). 

Lithium alone is rarely successful in treating schizophrenia, but adding it to an antipsychotic may salvage an otherwise treatment-resistant patient. Carbamazepine may work equally well when added to an antipsychotic drug. 

Polydipsia and polyuria are common but reversible concomitants of lithium treatment, occurring at therapeutic serum concentrations. The principal physiologic lesion involved is loss of responsiveness to antidiuretic hormone (nephrogenic diabetes insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but responds to amiloride. 

Hyperparathyroidism was considered a possible cause of treatment-resistant manic psychosis in a patient taking lithium (663). 

Hoogenberg K, Beentjes JA, Piers DA. Lithium as an adjunct to radioactive iodine in treatment-resistant Graves thyrotoxicosis. Ann Intern Med 1998 129(8) 670. 

Bschor T, Lewitzka U, Sasse J, et al. Lithium augmentation in treatment-resistant depression clinical evidence, serotonergic and endocrine mechanisms. Pharmacopsychiatry. 2003 36(suppl 3) S230—S234. 

By a lithium treatment at 300° C the intrinsic ZnO crystals with a resistivity of about 10 2 cm reached resistivities up to 10 0 cm. However, p-type... 

Observational studies Beneficial effects have been reported in patients with schizophrenia (n = 10) and schizoaffective disorder (n = 10) who were treated with a combination of clozapine and lithium (68). When lithium (serum lithium concentration titrated to at least 0.5 mmol/1) was added to clozapine 100—800 mg/day there was a positive effect in the patients with treatment-resistant schizoaffective disorder, but not in the patients with schizophrenia. 

The addition of lithium in treating major depressive disorder in patients unresponsive to antidepressant drugs has been discussed, and it has been noted that about 50% of patients respond to lithium augmentation in 2 1 weeks (71), while others have pointed to the absence of controlled data for this treatment in bipolar depression, while nevertheless recommending its use (72). In summary, there are data that support the use of lithium augmentation for treatment-resistant unipolar major depression. However, the data are not robust and are based on only a few hundred patients. Placebo-controlled studies of lithium augmentation for treatment-resistant bipolar depression are lacking (73). 

The addition of lithium to other drug therapy has been studied in 92 patients with treatment-resistant major depression taking nortriptyline (97). Non-responders to nortriptyline (n = 35) were randomized to added lithium or placebo there was no significant difference. 

In 12 healthy volunteers, there were no clinically significant alterations in blood concentrations of lithium or nefazodone and its metabolites when the drugs were coadministered (587). The addition of lithium for 6 weeks to nefazodone in 14 treatment-resistant patients produced no serious adverse effects and no dropouts (588). Lithium augmentation of nefazodone in 13 treatment-resistant depressed patients was associated with a variety of annoying adverse effects, but none led to treatment withdrawal (589). 

Seizures and other neurological effects have been described in a few cases when lithium was added to clozapine (626), but in other instances the combination was beneficial in overcoming treatment resistance or attenuating clozapine-induced leukopenia. Five treatment-resistant patients were treated successfully with a combination of clozapine and lithium with no clinically significant adverse events (627). However, a 59-year-old woman developed neurotoxic symptoms 3 days after lithium was added to clozapine the symptoms resolved when both drugs were stopped and recurred with rechallenge (628). 

Lithium is one of the most useful adjunctive agents to augment antidepressants for treatment-resistant unipolar depression... 

Lithium is also used to augment the action of antidepressants in treatment-resistant depression (see p. 375). 

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