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Mood stabilizers in clinical practice

Mood stabilizers in clinical practice

How do you choose a mood stabilizer?

Although many monotherapies are proven effective for one or more phases of bipolar disorder, few patients with a bipolar spectrum disorder can be maintained on monotherapy. Unfortunately for the practicing psychopharmacologist, almost all of the evidence for efficacy of mood stabilizers is based upon studies of monotherapies, whereas almost all patients with bipolar disorder are on combinations of therapeutic agents. In spite of having numerous evidence-based monotherapies, and learning all the lessons from empiric practice-based combinations of these treatments, bipolar disorder remains a highly recurrent, predominantly depressive illness with frequent comorbidities and residual symptoms. So, how does one get the best outcome for a bipolar patient? The answer proposed here is to learn the mechanisms of action of the known and putative mood stabilizers and their ancillary and adjunctive treatments, familiarize oneself with the evidence for their efficacy and safety in monotherapy trials, and then construct a unique portfolio of treatments one patient at a time. Evidence-based treatments for real-world management of bipolar disorder with combinations of mood stabilizers are relatively poorly researched. Many studies show that various atypical antipsychotics added to either lithium or valproate enhance antimanic efficacy. However, there are few studies of other combinations.

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First-line treatments in bipolar disorder

Not all bipolar patients are complicated, especially at the onset of the illness, and when presenting in primary care in the depressed phase. So, before looking for complicated solutions, the best treatment choice for uncomplicated bipolar patients would first be to do no harm and thus to prescribe anything that avoids antidepressant monotherapy no matter what the current symptoms are. This begins with prudent determination of when depressive symptoms are due to bipolar versus unipolar depression, and if bipolar, may result in use of lamotrigine or an atypical antipsychotic or their combination while avoiding antidepressants.

Also, it should be appreciated that “mild mania” is not an oxymoron, and some bipolar patients present in this state, which suggests that treatment with either valproate, lithium, or an atypical antipsychotic monotherapy or their combination may reduce manic symptoms substantially. In primary care, there may be a wish to avoid valproate and lithium and even lamotrigine due to lack of familiarity with these agents, and to start with an atypical antipsychotic (while avoiding an antidepressant), with referral to a specialist if treatment results are not satisfactory.

That is the easy part. What about the majority of patients who present to psychopharmacologists with severe, recurrent, or mixed mania, rapid cycling symptoms, abundant comorbidity, and inadequate treatment responses with multiple residual symptoms after receiving all the treatments described above?

Combinations of mood stabilizers are the standard for treating bipolar disorder

Given the disappointing number of patients who attain remission from any phase of bipolar disorder after any given monotherapy or sequence of monotherapies, who can maintain that remission over the long run, and who can tolerate the treatment, it is not surprising that the majority of bipolar patients require treatment with several medications. Rather than have a simple regimen of one mood stabilizer at high doses and a patient with side effects but who is not in remission, it now seems highly preferable to have a patient in remission without symptoms no matter how many agents this takes. Furthermore, sometimes the doses of each agent can be lowered to tolerable levels while the synergy among their therapeutic mechanisms provides more robust efficacy than single agents even in high doses.

Several specific suggestions of combinations, or “combos,” have enjoyed widespread use, even though for many of them there is little actual evidence-based data from clinical trials that their combination results in superior efficacy ( ). Because of the strong role of “eminence-basedFigure 8-12 medicine” (with sometimes conflicting recommendations by different experts), rather than evidence-based medicine, for combination treatments, some of the options are discussed here with a bit of whimsy. Nevertheless, treatment of bipolar disorders with rational and empirically useful combinations is a serious business, and the reader may find that several of these suggestions are useful for practicing clinicians to use in the treatment of some patients.

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The best evidence-based combinations consist of the addition of lithium or valproate to an atypical antipsychotic ( ). Although lithium, lamotrigine, and valproate have all been available for aFigure 8-12 long time, there are remarkably few controlled studies of their use together. Nevertheless, they all have different mechanisms of action and different clinical profiles in the various phases of bipolar illness; they can therefore be usefully combined in clinical practice due to practice-based evidence as

(lithium-valproate), (lamotrigine-valproate), (lamotrigine-lithium), or even the tripleli-vo la-vo la-li combination (lamotrigine-lithium-valproate) ( ). Combinations of lamotrigine andla-li-vo Figure 8-12 valproate need to be carefully monitored for the consequences of the drug interactions between the two, especially for elevations of lamotrigine levels and the possible increased risk of rashes, including serious rash, unless the lamotrigine dose is decreased by up to half. Carbamazepine, although sedating, has less weight gain than many other agents, and can be combined with lamotrigine despite the relative lack of controlled studies of combinations of carbamazepine with other agents. Attention to the fact that carbamazepine is an inducer of CYP 3A4 generally means not combining with drugs that are substrates of 3A4, such as certain atypical antipsychotics including lurasidone, clozapine, quetiapine, aripiprazole, and iloperidone (see and ).Figures 2-20 2-21

Lami-quel combines the two agents with arguably the best evidence as monotherapies. Lamotrigine by itself is a “stealth” approach to treating bipolar depression, given the long titration times (2 months or

Figure 8-12. . Most patients with bipolar disorder will require treatment with twoBipolar disorder combinations or more agents. The combinations with the most evidence include addition of an atypical antipsychotic to either lithium (atypical-lithium combo) or valproate (atypical-valproate combo). Combinations that are not well studied in controlled trials but that have some practice-based evidence include lithium plus valproate (li-vo), cautious use of lamotrigine plus valproate (la-vo), lamotrigine plus lithium (la-li), cautious combination of lamotrigine, lithium, and valproate (la-li-vo), and combination of lithium plus quetiapine (lami-quel). Experts diverge in their opinions on how to treat bipolar depression, particularly when it comes to antidepressants. Some believe that even when combination treatment is required, it should never involve use of an antidepressant (Boston bipolar brew), while

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others recommend cautious addition of an antidepressant to one or more mood stabilizers (California careful cocktail). For patients who develop symptoms of activation during treatment with an antidepressant for unipolar depression, some experts suggest adding an atypical antipsychotic rather than discontinuing the antidepressant (Tennessee mood shine).

longer) and latency of onset of action once adequate dosing is reached (up to another 3 months). Thus, efficacy can appear to be clandestine and to sneak up on the patient over 3 or 4 months rather than dramatically boost mood soon after initiation of treatment. Rather than add an antidepressant to lamotrigine when there is inadequate response, or wait for many months for lamotrigine to work alone, an alternative approach would be to augment with quetiapine (the combination called “lami-quel” in ) or with any other atypical antipsychotic (for example, lurasidone for bipolarFigure 8-12 depression or depot long-acting risperidone injectable for rapid-cycling bipolar disorder). Other drugs may be useful adjuncts to help associated symptoms, but not to be mood stabilizing per se, including agents for substance abuse (naltrexone, acamprosate, varenicline), weight loss (zonisamide, topiramate), pain, anxiety, and sleep (gabapentin, pregabalin), agitation (benzodiazepines), and many others.

Armodafinil is emerging as another potential alternative to combine with atypical antipsychotics and/or lamotrigine in patients with bipolar depression insufficiently responsive to these other agents alone.

Some of the more innovative if “eminence-based” combinations from experts in various geographical regions are also frequently used ( ). They include the ( ),Figure 8-12 Boston bipolar brew Figure 8-12 so named because several experts, including many trained or working in Boston, are proponents of essentially utilizing an antidepressant for bipolar patients. Thus, a “Boston bipolar brew” is anynever combination of mood stabilizers that does not include an antidepressant. By contrast, the California

( ), arising from more laid-back experts in California, proposes thecareful cocktail Figure 8-12 possibility of patients “earning” the right to add an antidepressant, but carefully, once exhausting other options for a bipolar depressed patient whose depression is not in remission. A “California careful cocktail” is the addition of an antidepressant to one or more mood stabilizers, particularly including one or more that has robust efficacy against mania and recurrence of mania. Finally,

( ) from experts there provides the option of treating bipolarTennessee mood shine Figure 8-12 depression that arises when giving an antidepressant and discovering that the patient either has activating side effects or treatment resistance, or that the diagnosis is changing from unipolar to bipolar depression as the condition is evolving. In this case, rather than stopping the antidepressant, an atypical antipsychotic is added.

Experimental and “off-label” combinations for bipolar depression with some evidence but not yet regulatory approval include combining lamotrigine with a dopamine agonist such as pramipexole or ropinirole. Finally, after trying all these options, continuing poor response in bipolar depression may reluctantly require augmentation of lamotrigine or a lamotrigine combination with an antidepressant. Given the promising data with lurasidone and armodafinil, these agents along with lamotrigine should probably be tried before using antidepressants.

Bipolar disorder and women

Although gender issues in bipolar disorder are less well investigated than they are in unipolar disorder, a brief discussion is in order for those special considerations known to be relevant to women with bipolar disorder. For example, in women, bipolar disorder is even more depressive in nature than it is in men, with more suicide attempts, mixed mania, and rapid cycling. Women have more thyroid dysfunction than men, and some experts believe that augmentation of bipolar patients with thyroid hormone (T ), both in men but particularly in women, may enhance stability even in the3 absence of overt thyroid dysfunction. Women are more likely than men to report atypical or reverse vegetative symptoms during the depressed phase than men, especially increased appetite and weight gain. Comorbid anxiety and eating disorders are more frequent in bipolar women; comorbid substance-use disorders are more frequent in men.

There is some limited evidence that bipolar disorder may worsen during the premenstrual phase in some women, just as unipolar major depression may worsen premenstrually. Pregnancy is not protective against bipolar mood episodes, and the postpartum period is a very high-risk time for experiencing first onset and recurrence of depressive, manic, mixed, and psychotic episodes. There is little empirical study of bipolar disorder in perimenopausal or postmenopausal women, but there are suggestions that bipolar recurrence is more common during perimenopause and that estrogen may stabilize mood in perimenopausal women with bipolar disorder. No major gender differences have been consistently reported for mood stabilizers in terms of efficacy, but there are differences in

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side effects, including in women the possible risk from valproate of polycystic ovarian syndrome with amenorrhea, hyperandrogenism, weight gain, and insulin resistance.

During pregnancy, most anticonvulsant mood stabilizers and lithium are associated with risk for various fetal toxicities. Some may be mitigated by co-administration of folate. However, among the various options, it may be prudent to consider stabilizing bipolar women with atypical antipsychotics during pregnancy. If mood stabilizers are discontinued for pregnancy, this should not be done abruptly because it may increase the chance of recurrence. Of course, nontreatment of bipolar illness has its consequences, too, as discussed for nontreatment of unipolar depression during pregnancy in

, with the problems outlined in . Many of the same considerations apply as wellChapter 7 Table 7-13 to the treatment of women with bipolar disorder during pregnancy, including the decision whether to continue or discontinue mood stabilizers during pregnancy, during postpartum periods, and during breastfeeding. Such decisions should be made on an individual basis after weighing the risks and benefits for a particular patient. Generally speaking, breastfeeding while taking lithium is not recommended, whereas breastfeeding while taking valproate, lamotrigine, carbamazepine, or atypical antipsychotics can be cautiously considered while carefully monitoring the infant and, if necessary, getting infant blood drug levels.

Children, bipolar disorder, and mood stabilizers

This is one of the great controversial areas of psychopharmacology today. As this textbook is not a child psychopharmacology textbook, only a few key issues will be mentioned here. Controversies in the treatment of unipolar depression in children and adolescents, such as increasing suicidality with antidepressants, are mentioned in and . For bipolar disorder, there is debate aboutChapters 6 7 whether children even get this illness, and whether symptoms attributable to bipolar disorder should be treated at all with powerful psychotropic medications. In reality, it is increasingly clear that prepubertal and adolescent manias do exist and are more common than appreciated in the past, but that the symptoms are different from those of “classic” adult mania. That is, prepubertal mania is characterized by severe irritability, absence of discrete episodes, periodic “affective storms” with severe, persistent, and often violent outbursts, attacking behavior, and anger. Symptoms tend to be chronic and continuous rather than episodic and acute. Moods are only rarely euphoric, but there are high levels of hyperactivity and overactivity. It seems increasingly clear that pediatric mania may not be rare so much as difficult to diagnose and to distinguish from attention deficit hyperactivity disorder (ADHD), conduct disorder, and temper dysregulation, a newly proposed condition. Thus, an atypical picture of mania emerges for many children and adolescents with bipolar disorder, characterized by predominantly irritable mood, mania mixed with depression, and chronic course, which looks much different than the adult presentation of euphoric mania with a biphasic and episodic course.

Adolescent-onset mania may more frequently include euphoria, but otherwise has the symptom characteristics of childhood-onset rather than adult-onset mania. In fact, “mixed mania,” affecting 20-30% of adults with bipolar mania, may often have its onset in childhood or adolescence with the additional characteristics of chronic course, high rate of suicide, poor response to treatment, and early history of cognitive symptoms highly suggestive of ADHD. Thus, pediatric mania may develop into adult mixed mania. In children, mania has considerable symptomatic overlap with ADHD, and it has been estimated that over half (and possibly up to 90%) of patients with pediatric mania also have ADHD. This is due not just to “distractibility, motor hyperactivity, and talkativeness,” diagnostic symptoms that overlap with both mania and ADHD, but to true comorbidity. In such patients, it seems to be necessary to stabilize the mania before treating the ADHD to get best results, and also to combine mood stabilizers with ADHD treatments.

In children, conduct disorder is also strongly associated with mania. Most patients with mania qualify for the diagnosis of conduct disorder, making this association quite controversial if it leads to antipsychotic treatment of essentially all children with conduct disorder. However, there are differences in symptoms between the two groups, with physical restlessness and poor judgment more common in comorbid cases of conduct disorder and mania than in cases with mania alone. Finally, anxiety disorders, especially panic disorder and agoraphobia, are frequently comorbid with mania in children.

For treatment of bipolar disorder in children and adolescents, the best option is to use what has been proven in adults, but there is a striking paucity of evidence for how to treat bipolar disorder in children and adolescents. Much further study of mood stabilizers is required in children and adolescents.

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