Vaughan & Asburys General Ophthalmology, 17th ed.

Chapter 8. Mood stabilizers

   Definition of a mood stabilizer: a labile label

   Lithium, the classic mood stabilizer

   Anticonvulsants as mood stabilizers

    Anticonvulsants with proven efficacy in bipolar disorder

    Anticonvulsants with uncertain or doubtful efficacy in bipolar disorder

   Atypical antipsychotics as mood stabilizers: not just for psychotic mania

   Other agents used in bipolar disorder

    Benzodiazepines

    Modafinil and armodafinil

    Hormones and natural products

   Antidepressants: do they make you bipolar?

   Mood stabilizers in clinical practice

    How do you choose a mood stabilizer?

    First-line treatments in bipolar disorder

    Combinations of mood stabilizers are the standard for treating bipolar disorder

    Bipolar disorder and women

    Children, bipolar disorder, and mood stabilizers

   Future mood stabilizers

   Summary

In this chapter, we will define mood stabilizers and will review the various pharmacological mechanisms of action proposed for mood stabilizers. We will also discuss concepts about how to use these drugs in clinical practice, including strategies for what to do if initial treatments fail and how to rationally combine mood stabilizers with another drug. Our treatment of mood stabilizers in this chapter is at the conceptual level, not at the pragmatic level. The reader should consult standard drug handbooks (such as the companion Stahl’s Essential Psychopharmacology: the Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice.

Definition of a mood stabilizer: a labile label

“There is no such thing as a mood stabilizer” – FDA

“Long live the mood stabilizers” – prescribers

What is a mood stabilizer? Originally, a mood stabilizer was a drug that treated mania and prevented recurrence of mania, thus “stabilizing” the manic pole of bipolar disorder. More recently, the concept of mood stabilizer has been defined in a wide-ranging manner, from “something that acts like lithium,” to “an anticonvulsant used to treat bipolar disorder,” to “an atypical antipsychotic used to treat bipolar disorder,” with antidepressants considered as “mood de-stabilizers.” With all this competing terminology, and with the number of drugs for the treatment of bipolar disorder exploding, the term mood stabilizerhas become so confusing that regulatory authorities and some experts now suggest that it is best to use other terms for agents that treat bipolar disorder.

Rather than the term mood stabilizers, some would argue that there are drugs that can treat any or all of four distinct phases of the illness (Figures 8-1 and 8-2). Thus, a drug can be “mania-minded” and “treat from above” to reduce symptoms of mania, and/or “stabilize from above” to prevent relapse and recurrence of mania (Figure 8-1). Furthermore, drugs can be “depression-minded” and “treat from below” to reduce symptoms of bipolar depression, and/or “stabilize from below” to prevent relapse and recurrence of depression (Figure 8-2). Not all drugs proven to work in bipolar disorder have all four therapeutic actions. In this chapter, we will discuss agents that have one or more of these actions in bipolar disorder, and for historical purposes and simplification, refer to any of these agents as “mood stabilizers.”



Figure 8-1. Mania-minded treatments. Although the ideal “mood stabilizer” would treat both mania and bipolar depression while also preventing episodes of either pole, in reality there is as yet no evidence to suggest that any single agent can achieve this consistently. Rather, different agents may be efficacious for different phases of bipolar disorder. As shown here, some agents seem to be “mania-minded” and thus able to “treat from above” and/or “stabilize from above” – in other words, to reduce and/or prevent symptoms of mania.



Figure 8-2. Depression-minded treatments. Although the ideal “mood stabilizer” would treat both mania and bipolar depression while also preventing episodes of either pole, as mentioned for Figure 8-1, in reality there is as yet no evidence to suggest that any single agent can achieve this consistently. Rather, different agents may be efficacious for different phases of bipolar disorder. As shown here, some agents seem to be “depression-minded” and thus able to “treat from below” and/or “stabilize from below” – in other words, to reduce and/or prevent symptoms of bipolar depression.

Lithium, the classic mood stabilizer

Bipolar disorder has classically been treated with lithium for more than 50 years. Lithium is an ion whose mechanism of action is not certain. Candidates for its mechanism of action are various signal transduction sites beyond neurotransmitter receptors (Figure 8-3). This includes second messengers, such as the phosphatidyl inositol system, where lithium inhibits the enzyme inositol monophosphatase; modulation of G proteins; and most recently, regulation of gene expression for growth factors and neuronal plasticity by interaction with downstream signal transduction cascades, including inhibition of GSK-3 (glycogen synthase kinase 3) and protein kinase C (Figure 8-3).



Figure 8-3. Lithium’s mechanism of action. Although lithium is the oldest treatment for bipolar disorder, its mechanism of action is still not well understood. Several possible mechanisms exist and are shown here. Lithium may work by affecting signal transduction, perhaps through its inhibition of second-messenger enzymes such as inositol monophosphatase (right), by modulation of G proteins (middle), or by interaction at various sites within downstream signal transduction cascades (left).

However lithium works, it is proven effective in manic episodes and in maintenance of recurrence, especially for manic episodes and perhaps to a lesser extent for depressive episodes. Lithium is well established to help prevent suicide in patients with mood disorders. It is also used to treat depressive episodes in bipolar disorder as an augmenting agent to antidepressants for unipolar depression, as mentioned in Chapter 7, but is not formally approved for these uses. A number of factors have led to an unfortunate decline in the use of lithium in recent years, including the entry of multiple new treatment options into the therapeutic armamentarium for bipolar disorder, the side effects of lithium, and the monitoring burden that is part of prescribing lithium. The modern use of lithium by experts departs from its classic use as a high-dose monotherapy for euphoric mania, with lithium utilized now as one member of a portfolio of treatments, often allowing once-a-day administration and lower doses when combined with other mood stabilizers. Lithium has equal or better efficacy in bipolar disorder compared to valproate for manic, depressive, or mixed episodes, although valproate is often more frequently prescribed. Anticonvulsants including valproate have been controversially and not completely convincingly linked to causing suicidality, whereas lithium actually reduces suicide in patients with bipolar disorder. In fact, some provocative studies from Austria to Texas to Japan suggest that the more lithium mobilized by rain from rocks and soil and then dissolved in drinking water, the lower the suicide rate in the general population as well! Another potential use of lithium arises from the notion that inhibition of GSK-3 by lithium could theoretically inhibit the phosphorylation of tau (τ) proteins and thus slow the formation of plaques and tangles in Alzheimer’s disease. A few studies have suggested that lithium can prevent progression from mild cognitive impairment to Alzheimer’s disease and reduce phosphorylated τ levels, especially if given for a long period of time (> 1 year), and even at low doses. This remains controversial and needs replication in larger studies, but is certainly an interesting development to monitor.

Well-known side effects of lithium include gastrointestinal symptoms such as dyspepsia, nausea, vomiting, and diarrhea, as well as weight gain, hair loss, acne, tremor, sedation, decreased cognition, and incoordination. There are also long-term adverse effects upon the thyroid and kidney. Lithium has a narrow therapeutic window, requiring monitoring of plasma drug levels. Modern use of lithium often includes dosing at the lower end of the therapeutic window and combining lithium with other mood stabilizers.

Anticonvulsants as mood stabilizers

Based upon theories that mania may “kindle” further episodes of mania, a logical parallel with seizure disorders was drawn, since seizures can “kindle” more seizures. Thus, several anticonvulsants are used to treat bipolar disorder, some with better evidence of efficacy than others (Table 8-1). Since the first anticonvulsants tested, namely carbamazepine and valproate, proved effective in treating the manic phase of bipolar disorder, this has led to the idea than any anticonvulsant would be a mood stabilizer, especially for mania. However, this has not proven to be the case, as anticonvulsants do not all act by the same pharmacological mechanisms. Numerous anticonvulsants are discussed below, including not only those with proven efficacy in different phases of bipolar disorder but also those with dubious efficacy in bipolar disorder (Table 8-1).

Table 8-1 Anticonvulsant mood stabilizers



Anticonvulsants with proven efficacy in bipolar disorder

Valproic acid

As for all anticonvulsants, the exact mechanism of action of valproic acid (also, valproate sodium, or valproate) is uncertain; however, even less may be known about the mechanism of valproate than for other anticonvulsants. Various hypotheses are discussed here, and summarized in Figures 8-4 though 8-7. At least three possibilities exist for how valproic acid works: inhibiting voltage-sensitive sodium channels (Figure 8-5), boosting the actions of the neurotransmitter GABA (γ-aminobutyric acid) (Figure 8-6), and regulating downstream signal transduction cascades (Figure 8-7). It is not known whether these actions explain the mood-stabilizing actions, the anticonvulsant actions, the anti-migraine actions, or the side effects of valproic acid. Obviously, this simple molecule has multiple and complex clinical effects, and research is trying to determine which of the various possibilities explain the mood-stabilizing effects of valproic acid so that new agents with more efficacy and fewer side effects can be developed by targeting the relevant pharmacological mechanism for bipolar disorder.



Figure 8-4. Valproic acid. Shown here is an icon of the pharmacological actions of valproic acid, an anticonvulsant used in the treatment of bipolar disorder. Valproic acid (also valproate) may work by interfering with voltage-sensitive sodium channels (VSSCs), enhancing the inhibitory actions of γ-aminobutyric acid (GABA), and regulating downstream signal transduction cascades, although which of these actions may be related to mood stabilization is not clear. Valproate may also interact with other ion channels, such as voltage-sensitive calcium channels (VSCCs), and also indirectly block glutamate actions.



Figure 8-5. Possible sites of action of valproate on voltage-sensitive sodium channels (VSSCs). Valproate may exert antimanic effects by changing the sensitivity of VSSCs, perhaps by directly binding to channel subunits or inhibiting phosphorylating enzymes that regulate the sensitivity of these ion channels. Inhibition of VSSCs would lead to reduced sodium influx and, in turn, potentially to reduced glutamate excitatory neurotransmission, which is a possible mechanism for mania efficacy.



Figure 8-6. Possible sites of action of valproate on γ-aminobutyric acid (GABA). Valproate’s antimanic effects may be due to enhancement of GABA neurotransmission, perhaps by inhibiting GABA reuptake, enhancing GABA release, or interfering with the metabolism of GABA by GABA transaminase (GABA-T).



Figure 8-7. Possible sites of action of valproate on downstream signal transduction cascades. Valproate has been shown to have multiple downstream effects on signal transduction cascades, which may be involved in its antimanic effects. Valproate inhibits glycogen synthase kinase 3 (GSK-3), protein kinase C (PKC), and myristolated alanine-rich C kinase substrate (MARCKS). In addition, valproate activates signals that promote neuroprotection and long-term plasticity, such as extracellular signal-regulated kinase (ERK), cytoprotective protein B-cell lymphoma/leukemia-2 gene (BCL2), and GAP43.

One hypothesis to explain mood-stabilizing antimanic actions is the possibility that valproate acts to diminish excessive neurotransmission by diminishing the flow of ions through voltage-sensitive sodium channels (VSSCs) (Figure 8-5). VSSCs are discussed in Chapter 3 and illustrated in Figures 3-19 through 3-21. No specific molecular site of action for valproate has been clarified, but it is possible that valproate may change the sensitivity of sodium channels by altering their phosphorylation, either by binding directly to the VSSC or its regulatory units or by inhibiting phosphorylating enzymes (Figure 8-5). If less sodium is able to pass into neurons, this may lead to diminished release of glutamate and therefore less excitatory neurotransmission, but this is only a theory. There may be additional effects of valproate on other voltage-sensitive ion channels, but these are poorly characterized and may relate to side effects as well as to therapeutic effects.

Another idea is that valproate enhances the actions of GABA, by increasing its release, decreasing its reuptake, or slowing its metabolic inactivation (Figure 8-6). The direct site of action of valproate that causes the enhancement of GABA remains unknown, but there is good evidence that the downstream effects of valproate ultimately do result in more GABA activity, and thus more inhibitory neurotransmission, possibly explaining antimanic actions.

Finally, a number of downstream actions on complex signal transduction cascades have been described in recent years (Figure 8-7). Like lithium, valproate may inhibit GSK-3, but it may also target many other downstream sites, from blockade of phosphokinase C (PKC) and MARCKS (myristolated alanine-rich C kinase substrate), to activating various signals that promote neuroprotection and long-term plasticity such as ERK kinase (extracellular signal-regulated kinase), BCL2 (cytoprotective protein B-cell lymphoma/leukemia-2 gene), GAP43, and others (Figure 8-7). The effects of these signal transduction cascades are only now being clarified, and which of these possible effects of valproate might be relevant to mood-stabilizing actions is not yet understood.

Valproate is proven effective for the acute manic phase of bipolar disorder and is commonly used long term to prevent recurrence of mania, although its prophylactic effects have not been as well established as its acute effects in mania. Antidepressant actions of valproate have also not been well established, nor has it been shown to convincingly stabilize against recurrent depressive episodes, but there may be some efficacy for the depressed phase of bipolar disorder in some patients. Some experts believe valproic acid is more effective than lithium for rapid cycling and mixed episodes of mania. In reality, such episodes are very difficult to treat, and combinations of two or more mood stabilizers, including lithium plus valproate, are usually in order. As mentioned for lithium, valproate can also be utilized once a day in doses that are towards the bottom of the therapeutic range in combination with other mood stabilizers such as lithium to improve tolerability and compliance. For optimum efficacy, it may be ideal to push the dose of valproate, but no drug works if your patient refuses to take it, and valproic acid often has unacceptable side effects such as hair loss, weight gain, and sedation. Certain problems can be avoided by lowering the dose, but this will generally lower efficacy, and thus there may be the requirement to combine it with other mood stabilizers when valproate is given in lower doses. Some side effects may be related more to chronicity of exposure rather than to dose and thus may not be avoided by reducing the dose. This includes warnings for liver and pancreatic effects, fetal toxicities such as neural tube defects, concerns about weight gain and metabolic complications, and possible risk of amenorrhea and polycystic ovaries in women of childbearing potential. A syndrome of menstrual disturbances, polycystic ovaries, hyperandrogenism, obesity, and insulin resistance may be associated with valproic acid therapy in such women.

Carbamazepine

Carbamazepine (Figure 8-8) was actually the first anticonvulsant to be shown effective in the manic phase of bipolar disorder, but it did not receive formal FDA approval until recently as a once-daily controlled-release formulation. Although carbamazepine and valproate both act effectively on the manic phase of bipolar disorder (Table 8-1), they appear to have different pharmacological mechanisms of action, including different side-effect profiles. Thus, carbamazepine is hypothesized to act by blocking voltage-sensitive sodium channels (VSSCs) (Figure 8-8), perhaps at a site within the channel itself, also known as the α subunit of VSSCs (Figure 8-9). As mentioned earlier, VSSCs are discussed in Chapter 3 and illustrated in Figures 3-19 through 3-21. The hypothesized action of carbamazepine upon the α subunit of VSSCs (Figure 8-9) is different from the hypothesized actions of valproate on these sodium channels (Figure 8-5), but may be similar to how the anticonvulsants oxcarbazepine and its active metabolite eslicarbazepine also act.



Figure 8-8. Carbamazepine. Shown here is an icon of the pharmacological actions of carbamazepine, an anticonvulsant used in the treatment of bipolar disorder. Carbamazepine may work by binding to the α subunit of voltage-sensitive sodium channels (VSSCs) and could perhaps have actions at other ion channels for calcium and potassium. By interfering with voltage-sensitive channels, carbamazepine may enhance the inhibitory actions of γ-aminobutyric acid (GABA).



Figure 8-9. Binding site of carbamazepine. Carbamazepine is believed to bind to a site located within the open channel conformation of the voltage-sensitive sodium channel (VSSC) α subunit.

Although both carbamazepine and valproate are anticonvulsants and treat mania from above, there are many differences between these two anticonvulsants. For example, valproate is proven effective in migraine, but carbamazepine is proven effective in neuropathic pain. Furthermore, carbamazepine has a different side-effect profile than valproate, including suppressant effects upon the bone marrow, requiring initial monitoring of blood counts, and notable induction of the cytochrome P450 (CYP) enzyme 3A4. Carbamazepine is sedating and can cause fetal toxicity such as neural tube defects.

Lamotrigine

Lamotrigine (Figure 8-10) is approved as a mood stabilizer to prevent recurrence of both mania and depression. There are many curious things about lamotrigine as a mood stabilizer. First, the FDA has not approved its use for bipolar depression, yet most experts believe that lamotrigine is effective for bipolar depression. In fact, given the growing concern about antidepressants inducing mania, causing mood instability, and increasing suicidality in bipolar disorder, lamotrigine has largely replaced antidepressants as a first-line recommendation in most treatment guidelines for bipolar depression. In that regard, lamotrigine has transformed the treatment of this difficult phase of bipolar disorder as one of the very few agents that seem to be effective for bipolar depression based upon results seen in clinical practice rather than from evidence derived from clinical trials.



Figure 8-10. Lamotrigine. Shown here is an icon of the pharmacological actions of lamotrigine, an anticonvulsant used in the treatment of bipolar disorder. Lamotrigine may work by blocking the α subunit of voltage-sensitive sodium channels (VSSCs) and could perhaps also have actions at other ion channels for calcium and potassium. Lamotrigine is also thought to reduce the release of the excitatory neurotransmitter glutamate.

A second interesting thing about lamotrigine is that even though it has some overlapping mechanistic actions with carbamazepine, namely binding to the open channel conformation of VSSCs (Figures 8-9 and 8-11), lamotrigine is not approved for bipolar mania. Perhaps its actions are not potent enough at sodium channels, or perhaps the long titration period required when starting this drug makes it difficult to show any useful effectiveness for mania, which generally requires treatment with drugs that can work quickly.



Figure 8-11. Possible site of action of lamotrigine on glutamate release. It is possible that lamotrigine reduces glutamate release through its blockade of voltage-sensitive sodium channels (VSSCs). Alternatively, lamotrigine may have this effect via an additional synaptic action that has not yet been identified.

A third aspect of lamotrigine that is unusual for an antidepressant mood stabilizer is its tolerability profile. Lamotrigine is generally well tolerated for an anticonvulsant, except for its propensity to cause rashes, including (rarely) the life-threatening Stevens–Johnson syndrome (toxic epidermal necrolysis). Rashes caused by lamotrigine can be minimized by very slow up-titration of drug during initiation of therapy, avoiding or managing drug interactions such as those with valproate that raise lamotrigine levels, and by understanding how to identify and manage serious rashes, including being able to distinguish them from benign rashes (see discussion of lamotrigine in Stahl’s Essential Psychopharmacology: the Prescriber’s Guide).

Finally, lamotrigine seems to have some unique aspects to its mechanism of action (Figure 8-11), namely to reduce the release of the excitatory neurotransmitter glutamate. It is not clear whether this action is secondary to blocking the activation of VSSCs (Figure 8-11) or to some additional synaptic action. Reducing excitatory glutamatergic neurotransmission, especially if excessive during bipolar depression, may be a unique action of lamotrigine and explain why it has such a different clinical profile as a treatment from below and a stabilizer from below for bipolar depression.

Anticonvulsants with uncertain or doubtful efficacy in bipolar disorder

Oxcarbazepine/eslicarbazepine

Oxcarbazepine is structurally related to carbamazepine, but is not a metabolite of carbamazepine. Oxcarbazepine is actually not the active form of the drug, but a prodrug that is immediately converted into a 10-hydroxy derivative, also called the monohydroxy derivative, that most recently has been named licarbazepine. The active form of licarbazepine is the S enantiomer, known as eslicarbazepine. Thus, oxcarbazepine really works via conversion to eslicarbazepine.

Oxcarbazepine is well known as an anticonvulsant with a presumed mechanism of anticonvulsant action the same as that for carbamazepine, namely, binding to the open channel conformation of the VSSC at a site within the channel itself on the α subunit (as in Figure 8-9). However, oxcarbazepine seems to have some important differences from carbamazepine, including being less sedating, having less bone-marrow toxicity, and having fewer CYP 3A4 interactions, making it a more tolerable agent that is easier to dose. On the other hand, oxcarbazepine has never been proven to work as a mood stabilizer. Nevertheless, because of a similar postulated mechanism of action but a better tolerability profile, oxcarbazepine has been utilized “off-label” by many clinicians, especially for the manic phase of bipolar disorder. There is now active investigation of the active moiety eslicarbazepine as a potential mood stabilizer.

Topiramate

Topiramate is another compound approved as an anticonvulsant and for migraine, and recently in combination with bupropion for weight loss in obesity. Topiramate has been tested in bipolar disorder, but with ambiguous results (Table 8-1). It does seem to be associated with weight loss and is sometimes given as an adjunct to mood stabilizers that cause weight gain, but can cause unacceptable sedation in some patients. Topiramate is also being tested in various substance-abuse disorders, including stimulant abuse and alcoholism. However, topiramate is not clearly effective as a mood stabilizer, neither from evidence-based randomized controlled trials (which are not consistently positive) nor from clinical practice.

The reason that topiramate may not have the robust efficacy of valproate or carbamazepine in the manic phase, nor of lamotrigine in the depressed and maintenance phases of bipolar disorder, is that it has a different mechanism of action from any of these agents. The exact binding site for topiramate is not known (see Figure 10-19), but it seems to enhance GABA function and reduce glutamate function by interfering with both sodium and calcium channels, but in a different way and at a different site than the previously discussed anticonvulsants. In addition, topiramate is a weak inhibitor of carbonic anhydrase. Topiramate is now considered an adjunctive treatment for bipolar disorder, perhaps helpful for weight gain, insomnia or anxiety, or possibly for comorbid substance abuse, but not necessarily as a mood stabilizer per se. It is also under investigation, in combination with phentermine, as a treatment for weight loss in obesity, which will be discussed in Chapter 14.

Gabapentin and pregabalin

These anticonvulsants seem to have little or no action as mood stabilizers, yet are robust treatments for various pain conditions, from neuropathic pain to fibromyalgia, and for various anxiety disorders; they are discussed in more detail in Chapters 9 and 10, dealing with anxiety and pain. Gabapentin and pregabalin are now classified as α2δ ligands, since they are known to bind selectively and with high affinity to the α2δ site of voltage-sensitive calcium channels (VSCCs) (see discussion in Chapter 10, and Figures 10-14 through 10-18). It appears that blocking these VSCCs when they are open and in use causes improvement of seizures, pain, and anxiety but not stabilization of mood. That is, “use-dependent” blockade of VSCCs prevents the release of neurotransmitters such as glutamate in pain pathways and anxiety pathways and also prevents seizures, but does not appear to affect the mechanism involved in bipolar disorder, since clinical trials of these agents in bipolar disorder show unconvincing mood stabilization. However, many bipolar patients do experience chronic pain, anxiety, and insomnia, and gabapentin and pregabalin may be useful adjunctive treatments to effective mood stabilizers, even though they do not appear to be robustly effective as mood stabilizers themselves. This is not surprising given the very different mechanism of action of these compounds as selective α2δ ligands on calcium channels (Figures 10-14 through 10-18), compared to the mechanisms of proven mood stabilizers such as valproate, carbamazepine, and lamotrigine on sodium channels (discussed above).

Calcium channel blockers (L-type)

There are several types of calcium channels, not only the N or P/Q channels linked to secretion of neurotransmitters, targeted by α2δ ligands, and discussed in Chapter 3 (see Figures 3-23 and 3-24) but also L channels localized on vascular smooth muscle that are targeted by various antihypertensive and antiarrhythmic drugs commonly called “calcium channel blockers.” L-type channels are located on neurons where their function is still being debated, and some anecdotal evidence suggests that calcium channel blockers, especially dihydropyridine-type calcium channel blockers, may be useful for some patients with bipolar disorder.

Riluzole

This agent has anticonvulsant actions in preclinical models, but was developed to slow the progression of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Theoretically, riluzole binds to VSSCs and prevents glutamate release in an action similar to that postulated for lamotrigine (Figure 8-11). The idea is that diminishing glutamate release in ALS would prevent the postulated excitotoxicity that may be causing death of motor neurons in ALS. Excessive glutamate activity may be occurring not only in ALS, but may also occur in bipolar depression, although not necessarily so severely as to cause widespread neuronal loss.

Due to riluzole’s putative action on preventing glutamate release, it has been tested in case series in a number of treatment-resistant conditions hypothetically linked to excessive glutamate activity, including not only bipolar depression but also treatment-resistant unipolar depression and anxiety disorders, with some promising initial results. There is great need for another agent that has the same clinical effects as lamotrigine. The problem with riluzole is that it is quite expensive and has frequent liver-function abnormalities associated with its use.

Atypical antipsychotics as mood stabilizers: not just for psychotic mania

When atypical antipsychotics were approved for schizophrenia, it was not surprising that these agents would work for psychotic symptoms associated with mania, since the D2 antagonist actions predict efficacy for psychosis in general (discussed in Chapter 5). However, it was somewhat surprising when these agents proved effective for the core nonpsychotic symptoms of mania and for maintenance treatment to prevent the recurrence of mania. These latter actions are similar to lithium and various anticonvulsants that act by very different mechanisms. More surprising yet is that some atypical antipsychotics are effective for bipolar depression. The question that arises is, how do atypical antipsychotics work as mood stabilizers? Also, do they act as mood stabilizers by the same pharmacologic mechanism as they do as antipsychotics? Finally, do they work for the symptoms of mania by the same pharmacologic mechanisms as they do for bipolar depression?

Putative pharmacologic mechanism of atypical antipsychotics in mania and bipolar depression

The answer to the question of how atypical antipsychotics work in mania is that we do not really know (Figure 5-36). In fact, theories about atypical antipsychotic pharmacologic actions in bipolar disorder are less well developed than they are for schizophrenia, such as those discussed extensively in Chapter 5. Indeed, it is still a quandary how bipolar disorder itself can create seemingly opposite symptoms during various phases of the illness, as well as the combination of both manic and depressive symptoms simultaneously. Ideas about dysfunctional circuits in the depressed phase of bipolar disorder (discussed in Chapter 6 and illustrated in Figure 6-45) are contrasted with different dysfunctions in both overlapping and distinctive circuits during the manic phase of the illness (discussed in Chapter 6 and illustrated in Figure 6-48). Rather than being conceptualized as having activity that is simply “too low” in depression and “too high” in mania, the idea is that dysfunctional circuits in bipolar disorder are “out of tune” and chaotic. According to this notion, mood stabilizers have the ability to “tune” dysfunctional circuits, increasing the efficiency of information processing in symptomatic circuits, thus decreasing symptoms whether manic or depressed.

If so, the D2 antagonist or partial agonist properties of atypical antipsychotics as well as conventional antipsychotics may account for reduction of psychotic symptoms in mania, but the 5HT2A antagonist and 5HT1A partial agonist properties of atypical antipsychotics may account for reduction of nonpsychotic manic and depressive symptoms by some (but not all) atypical antipsychotics. This could occur via reduction of glutamate hyperactivity from overly active pyramidal neurons by 5HT2A antagonist actions (discussed in Chapter 5 and illustrated in Figure 5-15). This could reduce symptoms associated with glutamate hyperactivity, which could include both manic and depressive symptoms, depending upon the circuit involved. Anti-glutamate actions of atypical antipsychotics are consistent with the known pharmacologic mechanisms of several known anticonvulsants that are also mood stabilizers. Adding together different mechanisms that decrease excessive glutamate activity could explain the observed therapeutic benefits of combining atypical antipsychotics with proven anticonvulsant mood stabilizers.

Several other mechanisms are feasible explanations for how certain atypical antipsychotics work to improve symptoms in the depressed phase of bipolar disorder (discussed in Chapter 5 and illustrated in Figures 5-365-375-525-605-61). Thus, numerous mechanisms of different atypical antipsychotics can increase the availability of monoamine neurotransmitters serotonin, dopamine, and norepinephrine, known to be critical in the action of antidepressants in unipolar depression. There are very different pharmacologic properties of one atypical antipsychotic compared to another, and this could potentially explain not only why some atypical antipsychotics have different actions than others in bipolar disorder, but also why some bipolar patients respond to one atypical antipsychotic and not another. Thus, all atypical antipsychotics are approved for schizophrenia, and most are approved for mania, but only one for bipolar depression (quetiapine), with another one having multiple positive clinical trials in bipolar depression (lurasidone). Although these differences in mood-stabilizer approvals for individual atypical antipsychotics may be somewhat of an artifact of commercial considerations and lack of completion of clinical trials for some of the newer agents, it may also reflect differing portfolios of pharmacologic actions among those properties that might have antidepressant actions (Figure 5-36). Much further research must be completed before we will know the reason why atypical antipsychotics may work in mania or in bipolar depression. In the meantime, these agents as a class provide some of the broadest efficacy in bipolar disorder available, indeed broader than for most anticonvulsants and comparable or better than that for lithium. Increasingly, therefore, the treatment of bipolar disorder is not only with two or more agents, but with one of those agents being an atypical antipsychotic.

Other agents used in bipolar disorder

Benzodiazepines

Although benzodiazepines are not formally approved as mood stabilizers, they nevertheless provide valuable adjunctive treatment to proven mood stabilizers, especially in emergent situations. Intramuscular or oral administration of benzodiazepines can have a calming action immediately, and provide valuable time for mood stabilizers with a longer onset of action to begin working. Also, benzodiazepines are quite valuable for patients on an as-needed basis for intermittent agitation, insomnia and incipient manic symptoms. Skilled intermittent use can leverage the mood-stabilizing actions of concomitant mood stabilizers and prevent eruption of more severe symptoms and possibly avoid rehospitalization. Of course, benzodiazepines should be administered with caution, especially acutely to patients with comorbid substance abuse, or chronically to any patient. The mechanism of action of benzodiazepines on GABAAreceptors is discussed in further detail in Chapter 9.

Modafinil and armodafinil

The wake-promoting agents modafinil and the active enantiomer armodafinil have both been tested in bipolar depression with positive results. Large multicenter trials of armodafinil as adjunctive treatment to atypical antipsychotics in bipolar depression are promising. These agents, sometimes classified as stimulants but known to be blockers of the dopamine transporter (DAT), are discussed in greater detail in Chapter 11.

Hormones and natural products

The omega-3 fatty acids EPA (eicosapentanoic acid) and DHA (docosohexanoic acid) have been proposed as mood stabilizers, or as natural products that may boost the actions of proven mood stabilizers with few if any side effects. EPA is an essential fatty acid and can be metabolized to DHA, and is a normal component of a diet that contains fish. Both EPA and DHA are found in large quantity in the brain, especially in cell membranes. Recent investigations suggest that omega-3 fatty acids may inhibit PKC (protein kinase C), not unlike the actions described earlier for valproate and illustrated in Figure 8-7. Studies of omega-3 fatty acids are ongoing and suggestive, but they have not yet been proven effective in bipolar disorder.

Inositol is a natural product linked to second-messenger systems and signal transduction cascades, especially for the phosphatidyl inositol signals related to various neurotransmitter receptors such as the 5HT2A receptor. Inositol has been studied in bipolar disorder and in treatment-resistant bipolar depression, where it may be as effective as an augmenting agent to antidepressants as approved mood stabilizers such as lamotrigine and risperidone. Further studies of inositol are necessary.

The centrally active form of the vitamin folate, L-methylfolate, is discussed extensively in Chapter 7 and illustrated in Figures 7-71 through 7-74. L-Methylfolate could theoretically boost monoamine neurotransmitter function in bipolar depression, but has not been widely studied in controlled trials. An additional rationale for utilizing L-methylfolate in bipolar disorder is because several anticonvulsants interfere with folate absorption or folate metabolism. Thus, bipolar patients who are partial responders to mood-stabilizing anticonvulsants (especially lamotrigine, valproate, and carbamazepine, but perhaps other anticonvulsants as well), or who lose their response, may be considered candidates for taking L-methylfolate.

Some investigators note that thyroid hormone, especially T3, may stabilize mood in some patients with bipolar disorder. This is not well researched and is somewhat controversial, especially for long-term use.

Antidepressants: do they make you bipolar?

Increasingly, it seems that antidepressants either do not work, or may worsen the situation for some patients who have bipolar disorder, causing destabilization of mood with induction of mania or hypomania, rapid cycling or mixed states or even suicidality. There is even an ongoing debate about whether antidepressants can cause someone to develop bipolar disorder who does not have this condition prior to taking an antidepressant, proposing that bipolar disorder could even be a complication of antidepressant treatment. Although this possibility is still under investigation, there is now little debate about the possibility that antidepressants, perhaps especially tricyclic antidepressants, can activate bipolar disorder in patients known to have a bipolar spectrum disorder.

Based upon current evidence, it seems likely that someone who develops bipolar disorder after taking an antidepressant is an individual who already has bipolar disorder, but the condition may have been previously undiagnosed, wrongly diagnosed, or “unmasked,” but not caused by antidepressant treatment. This is a particularly problematic issue for young patients, who may present with unipolar depressive symptoms before they express any manic or hypomanic symptoms, and who may be particularly vulnerable therefore both to misdiagnosis and to antidepressant-induced activation and suicidality.

So how do you know to whom you can give an antidepressant? Recommendations for use of antidepressants in patients with known bipolar disorder, who are at risk for bipolar disorder, or who have had activation of mania on antidepressants are still evolving. Currently, use of antidepressants for individuals in these situations must be considered on a case-by-case basis. Most experts agree that antidepressant monotherapy is generally to be avoided in such individuals, and that treatment of depression in bipolar disorder should start with other options such as lamotrigine, lithium, and/or atypical antipsychotics as monotherapies or in combination (Figure 8-12). Whether one can add an antidepressant to these agents in patients with bipolar depression who do not have robust treatment responses to these first-line agents is the subject of current debate. Many treatment guidelines do provide for use of antidepressants in combination with mood stabilizers, perhaps preferring bupropion the most and tricyclic antidepressants the least, but when to do this remains controversial, dependent somewhat on the results of ongoing studies, and upon where in the world you practice and were trained. Thus, common sense, integration of one’s clinical experience, and keeping up with this evolving area of psychopharmacology is now considered the best practice.



Figure 8-12. Bipolar disorder combinations. Most patients with bipolar disorder will require treatment with two 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 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).

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.

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 (Figure 8-12). Because of the strong role of “eminence-based 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.

The best evidence-based combinations consist of the addition of lithium or valproate to an atypical antipsychotic (Figure 8-12). Although lithium, lamotrigine, and valproate have all been available for a 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 li-vo (lithium–valproate), la-vo (lamotrigine–valproate), la-li (lamotrigine–lithium), or even the triple combination la-li-vo(lamotrigine–lithium–valproate) (Figure 8-12). Combinations of lamotrigine and 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 Figures 2-20 and 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 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 Figure 8-12) or with any other atypical antipsychotic (for example, lurasidone for bipolar 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 (Figure 8-12). They include the Boston bipolar brew (Figure 8-12), so named because several experts, including many trained or working in Boston, are proponents of essentially never utilizing an antidepressant for bipolar patients. Thus, a “Boston bipolar brew” is any combination of mood stabilizers that does not include an antidepressant. By contrast, the California careful cocktail (Figure 8-12), arising from more laid-back experts in California, proposes the 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, Tennessee mood shine (Figure 8-12) from experts there provides the option of treating bipolar 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 (T3), both in men but particularly in women, may enhance stability even in the 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 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 Chapter 7, with the problems outlined in Table 7-13. Many of the same considerations apply as well 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 Chapters 6 and 7. For bipolar disorder, there is debate about 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.

Future mood stabilizers

As the pharmacologic targets for mood stabilizers are not well developed, new mood stabilizers tend to come from the same areas as current drugs: namely, new antipsychotics and new anticonvulsants. New research is also targeting novel ways to block glutamate action or to bind to the sigma-1 (σ1) site. Both ketamine and dextromethorphan act at these sites and are discussed in Chapter 7 (see also Figures 7-90through 7-94).

Summary

Mood stabilizers have evolved significantly in recent years. They include agents that are mania-minded and treat mania while preventing manic relapse, as well as agents that are depression-minded and treat bipolar depression while preventing depressive relapse. Numerous agents of diverse mechanisms of action are mood stabilizers, especially lithium, various anticonvulsants, and atypical antipsychotics. Because of limits to the efficacy and tolerability of current mood stabilizers, combination therapy is the rule and mood-stabilizer monotherapy the exception. Evidence is evolving for how to combine agents to relieve all symptoms of bipolar disorder and prevent relapse, but the treatment of bipolar disorder today remains as much a psychopharmacological art as a science.