Treatment of Elevated Mood With Medication
General issues
As described elsewhere (1), prescribing mental health medication is unlike prescribing other types of medication, for example, antihypertensives or antibiotics. Both patient and practitioner beliefs can dramatically color the prescribing process. On the basis of a family member’s experience with psychotropics, shared family beliefs, professional hearsay or media presentations about psychotropics, patients and even some practitioners may have biased viewpoints. Despite gradually improving teaching about mental health and psychiatry, many beliefs about what causes mental illness and what constitutes appropriate treatment can significantly affect the prescribing process. Patients have preconceived notions about what mental health medications can or cannot do, and what risks are involved. Some of the myths related to mental health medications are listed in Table 7.1.
Although these myths will not be explored in detail in this text, the reader is referred to the author’s other writings for specific discussion. Suffice it to say that in our population, belief in these myths abounds; and dealing with these misconceptions becomes an essential part of medication treatment of elevated mood. These general myths are further complicated by specific myths related to elevated mood, which are listed in Table 7.2.
TABLE 7.1 Myths about mental health medication | |||||||||
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TABLE 7.2 Common beliefs about medication and elevated mood | ||||||||||||||
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As part of any initial treatment session that involves medication prescription, it is wise for the clinician to ask the patient about concerns or questions before making specific recommendations. This can be phrased as follows:
If I were to suggest that medication would be helpful in treating the problems for which you came today, do you have any specific concerns about taking medication based on what you’ve read or what you’ve been told by your family and friends?
Although it is generally unnecessary to ask about each of the concerns mentioned in Table 7.2, when specific questions or concerns are raised, it is essential that they be addressed before the actual prescription is made.
Sample responses to each of the concerns listed in Table 7.2 are as follows:
Concerns about creativity, cognitive skills, or enjoyment. This is a common concern about mood medication. You are a person who has shown creativity, energy, and the ability for significant accomplishment. Clearly, we intend to keep those skills intact. Our goal will be to further enhance your creativity and productive activity by allowing you to be more consistent in mood and to channel your energies productively. We also want to target some of the more problematic behaviors such as … (Here, list presenting complaints such as irritability and anger, depressed episodes, impulsive behavior, or difficulty with relationships). Medication is not going to negatively affect your cognitive abilities or intelligence. In fact, if you are feeling consistently better, I would expect you would be able to use your innate traits more efficiently. Individuals who have problems with their moods can often increase their enjoyment of life when they can depend on their body and brain to regulate mood in a predictable and consistent manner.
Causing depression. Although my assessment is that you have been somewhat overly active and “over-revved” recently, there would be no benefit in allowing you to become depressed. Our goal is to gradually bring down this level of overactivity to a pace that is comfortable for you and the others around you. Together we will be watching for any signs of depression to make sure that it does not happen.
Concerns about making personality flat or boring. Any treatment that would make you flat or boring is certainly not desirable and not something I expect for you. Some people with elevated mood are exceptionally talkative and overly energetic. Medication we use would help you to be more stable and consistently productive. Those individuals who are used to living life in “overdrive” do find that they talk less to some extent and find it less desirable to work exceptionally long hours. The benefit, though, is that they also become better listeners and conversationalists, and often find themselves more productive in the hours that they work. Between the two of us, we will keep close watch on any changes that would occur from medication because our overall goal is to have you feel better and function better; being flat or boring doesn’t accomplish anything.
Concerns about dangerous side effects. Fortunately, side effects that occur with mood medications are more annoying than serious or life-threatening. If we start medication, we will discuss any side effects that are common and any unusual side effects that are significant. Most importantly, I want us to stay in contact and, if you have any concerns about negative effects from the medication, let me know so we can discuss them.
Concerns about permanent brain changes. We have virtually no evidence to suggest that medications for elevated mood will in any way permanently affect your neurochemistry or brain structure. Although sometimes symptoms recur when medications are stopped, you are unlikely to have irreversible behavioral changes.
Concerns about strong medication only for “crazy” people. When some of the medicines we use now were introduced 30 or 40 years ago, they were used primarily for hospitalized, very ill individuals in large doses. We have now come to understand that many of the same medicines in smaller doses can be useful for people with mild-to-moderate symptoms. Many productive and admired individuals take mental health medications, and those around them are not even aware of it. The most important thing now is to help you feel well and stable.
Concerns about lifelong medication. Although there are individuals who benefit from taking medication long term, that is not our plan initially. If we agree to start medication, we would do so for a defined period of time after which, together, we would decide to gradually decrease the dose and ultimately stop the medication.
What we do from that point forward depends on how you respond to stopping medication. For now, the decision to start medication is not a decision to take it indefinitely.
What we do from that point forward depends on how you respond to stopping medication. For now, the decision to start medication is not a decision to take it indefinitely.
How much medication is enough?
In a patient with elevated mood, the estimate of how much medication is sufficient must be judged individually for each patient. The bottom line answer to this question is that amount of medication that can be mutually negotiated between clinician and patient. Some of the negotiation between clinician and therapist about necessary levels of medication may involve a reevaluation and potential redefinition of what is normal. Many hypomanic patients have been functioning at an accelerated pace for months or years. Mood stabilizing or modulating medications may make them feel that they are being “slowed down,” although by society’s standards, they are only becoming “normal” with treatment.
The steroid analogy
A useful analogy during this stage of negotiations is that of an athlete who uses steroids.
A person with chronically elevated mood is similar to an athlete who has been using anabolic steroids over an extended period of time. Such a person may have become accustomed to levels of activity, strength, and performance that are “supernormal.” They often ignore the negative aspects of steroids, such as hormonal changes, rage episodes, liver damage, skin changes, baldness, feminization (for men)/masculinization (for women), depression, and erectile dysfunction. Used long enough, the person may even believe that it is “normal” to be able to run as fast, hit a ball as far, or lift as much weight as they can when they are taking steroids. When the steroids are stopped, they may feel somewhat slowed down or less strong, but there are significant positive trade-offs. Many of the side effects mentioned disappear and the risk of life-threatening conditions such as liver or prostate cancer are significantly reduced. Most individuals find that even if their athletic performance is lessened to some degree from not using steroids, their overall health, happiness, and functioning is considerably enhanced. The trade-off is well worth any diminished athletic activity. Similarly, with elevated mood, you may have been used to functioning at “120 miles per hour” throughout much of your life. Even if treatment does slow you to “100 miles per hour,” there will be significant enhancements to your overall functioning from this minimal “loss of speed.”
Can’t I just be a little manic?
This analogy is often followed by questions such as, “Can’t I just be a little manic?” or “Isn’t there a way to keep me going 120 miles an hour without the
risk?” The best reply is “That is a very common request but something I do not know how to do. It is no more possible than safely driving city streets at excessive speed, or using steroids without the health risks.”
risk?” The best reply is “That is a very common request but something I do not know how to do. It is no more possible than safely driving city streets at excessive speed, or using steroids without the health risks.”
No matter what amount of medication the therapist thinks is ideal, it is only with the concurrence and agreement of the patient that the ultimate regimen can be defined and maintained. When treating patients with seriously elevated mood or full mania, the amount of medication is often determined by what medication levels are necessary for minimizing a variety of reckless, dangerous, or impulsive behaviors. Safety, recklessness, and impulsivity are not always seen in a similar light by the patient, his family, or the clinician. With less severely ill elevated mood patients, the appropriate level of medication may be that which minimizes the presenting complaints but still permits some elevated mood or overactivity. In this case, target symptoms need to be identified and medications specifically aimed at minimizing or eliminating these target symptoms. Depending on the particular medication and the breadth of its effectiveness, any one medication may or may not treat other target symptoms or incidental manifestations of elevated mood.
Lastly, clinicians may view medication amounts as being optimal when it slows the patient’s speed of thought down to a level that permits psychotherapeutic intervention. If a patient is talking, thinking, and behaving so rapidly that they cannot listen to or incorporate psychotherapeutic interventions, medication levels are likely insufficient.
What is not a part of the equation when deciding how much medication is enough is the outdated notion that side effects must be evident in order to indicate that the medication is working. This old notion suggested that medications were ineffective unless doses that produced side effects were reached. Modern psychopharmacology, however, sees side effects as totally unwanted unless they can be serendipitously useful to the patient’s functioning and overall treatment (such as sedation from a mood stabilizing medication that might be useful in helping a patient with insomnia).
The art of medication management of individuals with elevated mood requires tact, skill, and often repetitive discussions to negotiate and renegotiate what is the appropriate and optimal level of medication.
Medication research considerations
In summarizing the current literature on the treatment of elevated mood with medication, there are several caveats and general issues to be taken into consideration by the clinician. These include the following:
Most research has been conducted on patients with bipolar I disorder exclusively or mixed groups of bipolar I and bipolar II. Evidence of effectiveness in bipolar I episodes of mania may or may not generalize to treatment of hypomania.
Although there are more randomized placebo-controlled studies (Class A data) for the treatment of elevated mood than there are for depressed mood
in bipolar disorder, clinicians are often guided by consensus guidelines from various groups. Consensus guidelines are those recommendations formulated from the opinions of national experts. These can be obtained in two different ways. The first, as exemplified by the Expert Consensus Guidelines, is a pure tabulation of the answers to mailed questionnaires. It is then an opinion poll and not “evidence” per se. It does, however, reflect how major thought leaders practice. The second form of consensus guidelines involves a gathering of experts coming together to present and discuss their recommendations in a group. The resulting document (e.g., the Texas Implementation of Medication Algorithms or TIMA guidelines) is the end product of their discussions. Here the experts may present data to back up their opinion. The group can interact and challenge one another in order to arrive at consensus. When consensus is not reached, a hierarchy of recommendations and divergent opinion is presented. Although it is not true “evidence” in the sense of a randomized, controlled trial, the process will produce recommendations that will carry more import than an opinion poll.
Because research on elevated mood is likely to have been performed on heterogeneous groups of patients as discussed in Chapter 2, even our current data may be on a somewhat shaky foundation.
Primary factors in choosing medication
Despite limitations and confounding factors, research does give us useful clinical guidelines for the management of elevated mood with medication. This portion of the chapter will be divided into several sections. The text will first focus on the general issues in regard to choosing medication, then review the consensus guidelines from various professional groups. This will be followed by discussion of the advantages and disadvantages of individual antimanic medications. Lastly, additional considerations affecting the choice of medications such as medication safety, tolerability, and side effects as well as choosing medications based on underlying temperament will be outlined.
When choosing medication treatment for elevated mood, the choice is determined by a variety of factors that may be different for individual patients (Table 7.3). Simply knowing that a medication is effective is, of course, vital. Other factors, however, as discussed subsequently can significantly alter a clinician’s pharmaceutical choice.
Target symptoms
On the basis of our theoretical assumptions, recent clinical practice has assumed that antimanic medications for elevated mood have effectiveness on the constellation of manic/hypomanic symptoms with equal effectiveness. Medication research has grouped patients with bipolar I and bipolar II disorders together regardless of the intensity of specific symptoms within the diagnosis. Someone with a predominant irritable elevated mood, therefore,
would be included in the same research protocol group with a patient who has primarily grandiose euphoric mania. Broad-based conclusions of medication effectiveness in an overall elevated mood group may or may not reflect equal effectiveness within subgroups of this population. Although there is limited research on which to firmly base clinical decisions at present, it is hoped that ongoing research will begin to separate phenotypic differences in ways that permit the clinician to identify the most appropriate treatment for specific target symptoms. Armed with this information, clinicians can more specifically choose the most effective medicine for the specific symptomatology such as irritability, sleeplessness, overactivity, grandiosity, impulsivity, and other symptoms of elevated mood. Steven Stahl’s concept that individual symptoms are determined by abnormalities in specific brain neurocircuitry, symptoms, and circuits fosters this manner of thinking (2).
would be included in the same research protocol group with a patient who has primarily grandiose euphoric mania. Broad-based conclusions of medication effectiveness in an overall elevated mood group may or may not reflect equal effectiveness within subgroups of this population. Although there is limited research on which to firmly base clinical decisions at present, it is hoped that ongoing research will begin to separate phenotypic differences in ways that permit the clinician to identify the most appropriate treatment for specific target symptoms. Armed with this information, clinicians can more specifically choose the most effective medicine for the specific symptomatology such as irritability, sleeplessness, overactivity, grandiosity, impulsivity, and other symptoms of elevated mood. Steven Stahl’s concept that individual symptoms are determined by abnormalities in specific brain neurocircuitry, symptoms, and circuits fosters this manner of thinking (2).
TABLE 7.3 Primary factors in choosing medication for mood | ||||||||||||||
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Prior response
As is the case in treating all psychiatric conditions with recurrent episodes, a prior history of positive response in a previous elevated mood episode will direct a clinician to strongly consider restarting the efficacious medication. This general principle may, however, be modified if the positive response was complicated by significant and/or serious side effects. If tolerability was impaired, another medication with a different side effect profile might be chosen. Also if a previously used medication was helpful for a period of time but then lost effectiveness, it may not be the best first choice for a symptomatic recurrence.
Medical comorbidity
Ongoing medical conditions or concurrent treatment with nonpsychiatric medications may also affect the choice of antimanic pharmaceuticals.
Such situations can direct a clinician toward a particular medication choice as well as away from a particular medication selection. For example, a patient who presents with elevated mood and a seizure disorder might preferentially be treated with an anticonvulsant that has antimanic properties such as sodium valproate, carbamazepine, or lamotrigine. A patient with ongoing hepatic dysfunction may have a less complicated course if lithium or lamotrigine is used to treat their elevated mood because both are excreted renally. Although the calcium channel blocker verapamil is not high on the list of antimanic treatments, it may become more desirable in a patient who suffers from hypertension or cardiac arrhythmia, in that both medical and mental health conditions may be treated simultaneously with one medication. Unstable type 1 diabetic patients with frequent fluctuations in salt and fluid balance might be more prone to changes in serum lithium levels, and therefore lithium might not be the best tolerated first choice for treatment of elevated mood in these patients.
Such situations can direct a clinician toward a particular medication choice as well as away from a particular medication selection. For example, a patient who presents with elevated mood and a seizure disorder might preferentially be treated with an anticonvulsant that has antimanic properties such as sodium valproate, carbamazepine, or lamotrigine. A patient with ongoing hepatic dysfunction may have a less complicated course if lithium or lamotrigine is used to treat their elevated mood because both are excreted renally. Although the calcium channel blocker verapamil is not high on the list of antimanic treatments, it may become more desirable in a patient who suffers from hypertension or cardiac arrhythmia, in that both medical and mental health conditions may be treated simultaneously with one medication. Unstable type 1 diabetic patients with frequent fluctuations in salt and fluid balance might be more prone to changes in serum lithium levels, and therefore lithium might not be the best tolerated first choice for treatment of elevated mood in these patients.
Safety and tolerability of medications are of crucial importance in choosing pharmaceuticals to treat elevated mood and will be discussed in more detail later in the chapter.
Using the patient’s underlying temperament to help determine the choice of medication is a relatively new concept. It makes sense however to utilize the broad panorama of the patient’s overall mood pattern to help determine the optimal treatment for a current index episode of elevated mood. This topic too will be discussed subsequently.
Secondary considerations in medication choice
Although not as important as the considerations mentioned earlier, other factors may also influence a clinician’s selection of medication as noted in Table 7.4.
In 21st century psychopharmacology, it is common to have information about first-degree biological relatives who may have been treated for mood conditions. Although a clinician would not automatically choose a medication
just because a close biological relative had responded to it, this history might be the deciding factor between two equivalently effective medications for the identified patient. Beyond the possible genetic underpinnings and biological likelihood of response, the presence of a positive response in a close family member may favorably predispose the patient psychologically toward this choice. The opposite is also true. If a family member had not had any response or significant side effects to a specific pharmaceutical, the patient may be biologically and/or psychologically negatively predisposed to such a choice.
just because a close biological relative had responded to it, this history might be the deciding factor between two equivalently effective medications for the identified patient. Beyond the possible genetic underpinnings and biological likelihood of response, the presence of a positive response in a close family member may favorably predispose the patient psychologically toward this choice. The opposite is also true. If a family member had not had any response or significant side effects to a specific pharmaceutical, the patient may be biologically and/or psychologically negatively predisposed to such a choice.
TABLE 7.4 Secondary factors in medication choice | ||||||||||
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Monotherapy is always preferential to combination therapy if the therapeutic effects are roughly equivalent. Modern treatment of elevated mood, however, is rarely accomplished through monotherapy. Intelligent, carefully selected combinations of treatments may provide significantly better treatment response than what one agent can provide. The “treat to remission” concept discussed in the subsequent text gives strong credence to the recommendation that combination therapy be used when significant mood symptoms are not ameliorated by one agent. In general, therapeutic advantages outweigh the disadvantages of combination treatment, such as an increased likelihood of side effects, poorer compliance, and increased expense. Specific combination treatments for elevated mood are difficult to evaluate from hard evidence. There is scant class A evidence comparing various combinations of treatment to each other except as compared to against monotherapy.
The cost of the newest (and often more effective) pharmaceuticals is significant and a factor that we must take into account when choosing a treatment. The availability of less expensive generic formulations, resources to pay out of pocket, as well as inclusion on insurance formularies become significant, although bothersome, factors affecting the clinician’s choice. Our most elegant diagnostic formulations and treatment regimens are useless if the patient cannot afford or cannot access the medications that we recommend and prescribe.
Lastly, patient preference is becoming a larger factor in the choice of pharmaceuticals. Whether it is because of family response or nonresponse, articles from the media and Internet, or discussion with other patients, patients come to treatment with specific biases for or against various medications for elevated mood. Although a secondary factor, clinicians cannot ignore that patients are much more favorably disposed to medications that they have positive expectations about and negatively predisposed to medications they fear or have heard will cause significant problems. Media advertising is common practice for antidepressant medication. Recently, the media has also begun advertising for bipolar medications. Such advertising may affect consumer expectation or feelings about a particular pharmaceutical choice.
Hypomania versus mania medication choice
Few would argue that effectiveness is of first and primary importance in choosing any pharmaceutical. Whether a patient is mildly to moderately
hypomanic or fully manic, no ineffective medication would be a sensible choice. Choosing medication for milder elevated mood states however, is perhaps much more influenced by considerations of tolerability than treatment of mania that often begins in the hospital and is instituted in inpatient settings. Hypomanic patients (who are often outpatients, and may have been overly active) may be much more attuned to issues of annoying side effects. They are also more likely to be noncompliant if side effects are prominent. Given that their hypomanic elevated mood states may be seen as a value and asset (at least when not out of control), they often are skeptical of the necessity for medicine at all. They will clearly be negatively predisposed to medication treatments that cause significant side effects.
hypomanic or fully manic, no ineffective medication would be a sensible choice. Choosing medication for milder elevated mood states however, is perhaps much more influenced by considerations of tolerability than treatment of mania that often begins in the hospital and is instituted in inpatient settings. Hypomanic patients (who are often outpatients, and may have been overly active) may be much more attuned to issues of annoying side effects. They are also more likely to be noncompliant if side effects are prominent. Given that their hypomanic elevated mood states may be seen as a value and asset (at least when not out of control), they often are skeptical of the necessity for medicine at all. They will clearly be negatively predisposed to medication treatments that cause significant side effects.
This is not to say that treatments for full mania are not, and should not be, influenced by possible side effects. When these treatments are undertaken in a controlled setting such as a hospital, it is often possible to monitor side effects more closely and if they are mild, continue treatment until they abate or are modified by changes in therapeutic regimen. The irony, therefore, is that in mildly elevated mood states, medication tolerability may be almost as important as effectiveness. A well-tolerated medicine that has a slightly decreased efficacy may be more acceptable to a hypomanic patient than a statistically more effective medication that has annoying side effects.
Treating to remission
A well-rooted concept in the literature of depression/anxiety treatment is that clinicians should not settle for improvement, but strive for elimination of all target symptoms. The literature is now replete with studies that suggest that when significant symptomatology is left untreated, the likelihood of symptomatic relapse is higher. This concept has only recently begun to be applied to bipolar disorder and elevated mood.
Information from the large national Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) gives strong support to the concept that “treating to remission” is necessary in bipolar disorder as well (3). A subset of the total number of patients focused on the 1,469 patients who had participated in the program for at least 2 years and had achieved recovery. While not specifically studying patients who achieved full remission per se, 48.5% of patients of this subgroup who had achieved recovery experienced relapse within a 2-year window despite the highest quality evidence-based care. This does not prove that treatment to remission would have lessened the frequency of these relapses, but it emphasizes the prevalence of recurrences and the need for aggressive, thorough treatment of symptoms.
Short-term, 3- to 4-week medication trials often do not permit full treatment of symptoms to remission. Comparing studies is confounded by the fact that different studies use different definitions of remission. Most investigators use a cutoff score (e.g., ≤12 on the Young Mania Rating Scale [YMRS]) for several weeks. Despite this lack of direct and comparable data, most reasonable
clinicians assume that the treatment that relieves the maximum number of symptoms most completely is desirable in this highly recurrent disease.
clinicians assume that the treatment that relieves the maximum number of symptoms most completely is desirable in this highly recurrent disease.
Off-label prescribing
As in all of psychiatry, prescribing medications for non-FDA approved, off-label uses is more the rule rather than the exception. Anticonvulsants, atypical antipsychotics, antidepressants, and benzodiazepines are all frequently prescribed for one or more symptoms of bipolar disorder with frequency, without a formal U.S. Food and Drug Administration (FDA) indication. In some cases, this is forward thinking, intelligent prescription, based on clinical experience that may precede formal studies and trials. At other times, however, it represents practice based on habit or hearsay with minimal clinical logic. Such off-label prescription is likely to continue in the foreseeable future, but can be made safer and more justified if the seven steps listed here are followed.
Seven steps to safer, more effective off-label prescribing (4):
1. Be familiar with evidence-based findings/guidelines.
2. Clarify your rationale for off-label prescription.
3. Obtain second opinion if indicated.
4. Perform risk-benefit analysis.
5. Obtain informed consent from patient or appropriate surrogate.
6. Document steps 1 through 5 in the patient’s record.
7. Monitor for known and unexpected adverse effects.
Following evidence-based guidelines such as those reviewed in this text is essential to understanding what has proved to be effective and what may not. Although it is not inappropriate to use medications for off-label indications, clinicians should be clear about why they are doing it. This may include lack of efficacy of on-label medications, a past history of response to the off-label drug or the presence of medical or comorbid conditions that make on-label medications less desirable. Although many off-label prescriptions are in common usage and can be justified on the basis of the clinician’s judgment alone, when an unusual or potentially risky choice is made, a second opinion supporting the decision may be useful. It is important to document the clinician’s thinking in the written record on any off-label prescription including the fact that the patient was informed of the off-label use with its potential risks and rewards. As with any medication, the patient should be monitored for side effects or untoward responses as there may be some additional clinician liability when serious untoward reactions occur in an off-label prescription.
FDA-approved antimanic treatments
Before considering the recommendations of various expert groups the reader must be familiar with those compounds that have FDA approval
for treating the elevated mood states of bipolar disorder. These are shown in Table 7.5.
for treating the elevated mood states of bipolar disorder. These are shown in Table 7.5.
TABLE 7.5 FDA-approved medications for the treatment of mania | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Overlapping terms
Before discussing specific recommendations for specific phases of bipolar disorder, it is crucial to identify some terms that have been variously applied to mood states of elevation and depression. The term elevated mood is a generic one and includes those states of mania, hypomania, and mixed mania, both syndromal and subsyndromal.
As we discuss specific medications, some terms bear definition. Ketter and Calabrese have proposed a nomenclature using “above-baseline” states to refer to diagnosable elevated mood conditions and “below baseline” to refer to depressive states (6,7). Other thought leaders have used the term treating from above to mean medications which have more prominent effects on elevated mood states than on depressed states. Treating from below then means medications that preferentially treat depressed mood states. Ketter and Calabrese label these as stabilization from above-baseline mood states and stabilization from below-baseline mood states. Other potential mood labels include up-dominated mood patterns and down-dominated mood patterns. The former refers to a phenotypically bipolar person who has predominantly
elevated mood episodes and the latter to an individual who has predominantly depressive mood episodes.
elevated mood episodes and the latter to an individual who has predominantly depressive mood episodes.
Consensus guidelines
Four separate guidelines will be summarized here, followed by the author’s consolidated recommendation regarding individual agents.
Texas Implementation of Medication Algorithms (TIMA) guidelines
The Texas Consensus Conference Panel on medication treatment of bipolar disorder devised the Texas Implementation of Medication Algorithms (TIMA Guidelines). Initially published in 2002, they have been updated in 2006. The recommendations for the treatment of above-baseline mood episodes, that is, hypomanic, manic, and mixed episodes in bipolar I disorder are summarized in Table 7.6.
This algorithm is divided into four stages and separates at Stage 1 into treatments recommended for euphoric elevated mood and those recommended for mixed elevated mood. Stage 1 recommends lithium, valproate, aripiprazole, quetiapine, risperidone, or ziprasidone as first-line treatment for euphoric mania, with olanzapine or carbamazepine also considered first line, but separated because of their side effect burden.
For mixed mania, valproate, aripiprazole, risperidone, and ziprasidone are first-line treatments. When there is no response to one or more of the stage 1 treatments, the patients are moved to stage 2.
This stage incorporates two-drug combinations that include lithium plus valproate, lithium plus an atypical antipsychotic, or valproate plus an antipsychotic. Specifically the recommended antipsychotics are olanzapine, quetiapine, risperidone, and ziprasidone. Aripiprazole was not identified in this stage because of the absence of evidence at the time of these recommendations.
Failure to respond to stage 2 therapies lead to the recommendations in stage 3, in which any two drugs from the list of lithium, valproate, atypical antipsychotics, carbamazepine, oxcarbazepine, and typical antipsychotics can be combined as long as it is not two atypical antipsychotics together and not clozapine.
When stage 3 treatments are ineffective, the recommendations are for the use of electroconvulsive therapy (ECT), adding clozapine to the combinations in stage 3 or using three-drug combinations from the list in stage 3.
Expert consensus guideline
Published in 2000 by Keck et al. and updated in 2004 (8), this guideline is a composite of questionnaires returned by 47 experts in the field of the
treatment of bipolar disorder. They were asked to rate mood medications on a scale of 1 to 9, with
treatment of bipolar disorder. They were asked to rate mood medications on a scale of 1 to 9, with
TABLE 7.6 Treatment of acute manic/hypomanic/mixed episodes in bipolar I disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||
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1 being extremely inappropriate;
2 and 3 being usually inappropriate treatment, rarely used;
4 to 6 being equivocal, a second-line treatment;
7 to 8 being a first-line treatment that would often be used;
9 being a treatment of choice.
Specifically in regard to elevated mood, the experts were asked to separate out treatments for acute mania from maintenance treatment for bipolar I disorder.
TABLE 7.7 Expert consensus guideline: initial treatment for first manic episode | ||||||||||||||||||||||||||||||||||||
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On the basis of clinical presentation of the initial manic episode, the responses were divided into preferred and alternate strategies for initial and maintenance therapies as shown in Tables 7.7 and 7.8.
For purposes of these tables, a mood stabilizer is defined as an agent that had been previously defined in 2000 in the first version of these guidelines. Specifically, carbamazepine, lithium, and valproate are listed as “mood stabilizers.” Although the categories are broken out into classic euphoric mania, mixed mania, mania with a history of rapid cycling, and mania with psychosis, many of the preferred treatments are similar. Specifically, the
preferred mood stabilizers are divalproex or lithium with carbamazepine as an alternative. When atypical antipsychotics are used, olanzapine, risperidone, and quetiapine are preferred with aripiprazole and ziprasidone as alternatives. Classic euphoric mania can be treated with a mood stabilizer alone, a mood stabilizer plus an atypical antipsychotic, or with possible short-term augmentation with benzodiazepines. An alternative to these preferred strategies is an atypical antipsychotic alone.
preferred mood stabilizers are divalproex or lithium with carbamazepine as an alternative. When atypical antipsychotics are used, olanzapine, risperidone, and quetiapine are preferred with aripiprazole and ziprasidone as alternatives. Classic euphoric mania can be treated with a mood stabilizer alone, a mood stabilizer plus an atypical antipsychotic, or with possible short-term augmentation with benzodiazepines. An alternative to these preferred strategies is an atypical antipsychotic alone.
TABLE 7.8 Expert consensus guideline: preferred agents | ||||||||||||||||||||||||||||||
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TABLE 7.9 Expert consensus guideline: maintenance strategies after a manic episode | ||||||||||||||||||
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The Expert Consensus Guidelines for maintenance strategies are shown in Table 7.9.
As shown in the preceding text, the preferred maintenance strategies depend on the response to acute-phase treatment. If a patient responded to a mood stabilizer alone, it is to be continued with the possibility of adding psychotherapy, and possibly lowering the dose of the mood stabilizer over time. If an atypical antipsychotic was used alone, there is a parallel strategy to continue the atypical antipsychotic, while at the same time adding psychotherapy or lowering the atypical antipsychotic over time. When a mood stabilizer plus an atypical antipsychotic is used in the acute-phase treatment, the preferred strategy is to continue both at the same dosage and add psychotherapy. Alternatively the patient could have the atypical antipsychotic tapered and discontinued over time while maintaining the mood stabilizer.
American Psychiatric Association and British Association for Psychopharmacology guidelines
The guidelines developed by the American Psychiatric Association (APA) and the British Association for Psychopharmacology (BAP) are shown in Table 7.10. They are grouped together because they made their guidelines on
the basis of level of severity of the symptoms, which is different than the other guidelines.
the basis of level of severity of the symptoms, which is different than the other guidelines.
Although there are some differences, these two guidelines have significant agreement and in many ways agree with the Expert Consensus guidelines. Specifically for severe illness, a combination therapy of lithium or divalproex plus an antipsychotic are the preferred treatments with carbamazepine as an alternative. Benzodiazepines can be added as a short-term adjunctive therapy.
Maintenance treatments following an initial episode of mania are shown in Table 7.11.
Again there is considerable overlap and agreement between these two guidelines and the Expert Consensus guidelines for maintenance treatment. Of note is the addition of ECT in both the APA and BAP guidelines if the acute response is inadequate. Also psychosocial interventions are specifically added by both bodies.
Having discussed the various guidelines formulated by official and expert bodies, we will now look at the various individual medications in their treatment of acute mania.
Lithium
As one of the oldest medications available to treat bipolar disorder and having been in clinical usage for over 50 years, lithium has abundant data support for its usefulness in acute mania and remains one of the first-line agents in this phase of the illness. Response rates (defined as >50% improvement in manic symptoms) fall between 49% and 70% (10). Bowden et al. showed lithium’s effectiveness as compared to placebo as early as day 10 (11). These are several of many studies showing lithium’s effectiveness. Although lithium has proven therapeutic effect, it is used as monotherapy for a relatively small group of patients with bipolar disorder because of side effects or comorbid medical conditions. Polyuria, polydipsia, hand tremor, and long-term effects on kidneys and thyroid are known complications. The narrow therapeutic index makes lithium toxicity a significant possibility if lithium levels are not followed carefully. Lithium has been shown to be specifically effective under the following conditions (12,13):
It is begun during the first few episodes of the illness.
Depressive symptoms do not accompany mania.
Comorbid medical or psychiatric problems are absent.
A family history is positive for lithium-responsive bipolar disorder.
A further advantage of lithium is that it decreases the risk of suicidal behavior in individuals with bipolar disorder. That is particularly important in a bipolar population that has elevated suicide rates particularly during the early phases of the illness (13).
TABLE 7.10 Evidence-based treatment guidelines for acute mania or mixed episodea | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Carbamazepine
Interest in the use of the carbamazepine molecule has been long standing and second only to lithium. Although several studies were conducted in the 1980s regarding the usefulness of carbamazepine (16,17), a resurgence of its popularity has emerged with the use of carbamazepine extended-release monotherapy under the trade name of Equetro. In a study by Weisler et al. (18), carbamazepine showed a 41.5% response rate with manic and mixed mania patients as compared to 22.4% for placebo. Response was defined as ≥50% decrease in the YMRS. Whether in the traditional or extended-release forms,
the usage of carbamazepine has been complicated by the fact that the molecule induces metabolism of many other agents based on P450 mechanisms. Liver toxicity, agranulocytosis, and Stevens-Johnson syndrome are infrequent, but known serious complications of the use of carbamazepine.
the usage of carbamazepine has been complicated by the fact that the molecule induces metabolism of many other agents based on P450 mechanisms. Liver toxicity, agranulocytosis, and Stevens-Johnson syndrome are infrequent, but known serious complications of the use of carbamazepine.
Oxcarbazepine, the keto- analog of carbamazepine (sometimes dubbed son of Tegretol) under the brand name Trileptal has shown possible efficacy, but has not been proved in randomized controlled trials (RCTs). Its demonstrated effectiveness, therefore, remains questionable. It does have a side effect advantage over carbamazepine in that it does not appear to carry the risk of liver toxicity, induction of the cytochrome P450 system, or leukopenia. It does, however, have a slightly increased incidence of hyponatremia.
Divalproex
Sodium valproate in the divalproex formulation has been commonly used over the past 12 years in the acute treatment of mania or mixed mania. In the initial studies leading to its approval, Bowden et al. showed improvement in manic symptoms as compared to placebo as early as day 5 as measured by the SADS-C(Schedule of Affective Disorders and Schizophrenia-Change Version) (11). Although initially thought to be more effective in patients with rapid cycling (19), more recent data (20) suggests that divalproex may be no more effective than lithium in persons with rapid cycling. Other populations in which divalproex is thought to have an advantage over lithium include the presence of depressive features during mania (21) and bipolar disorder complicated by comorbid alcohol dependence (22,23,24). A further advantage of this compound is that it can be given as a loading dose (20 to 30 milligrams per kilogram of body weight). This is particularly useful for severely ill hospitalized manic patients. Common side effects include nausea, diarrhea, weight gain, sedation, hair loss and thrombocytopenia. Pancreatitis is a rare but serious side effect.
Antipsychotics
Although first-generation antipsychotics have long been used for rapid treatment of psychosis and agitation in severe mania, these medications have been largely supplanted by the second-generation antipsychotics that have distinct safety advantages and some therapeutic advantages beyond antipsychotic activity. Because of the blockade of the postsynaptic 5HT2A receptor and agonism at the 5HT1A receptor, these agents have active enhancement of serotonin levels leading to positive mood effects and beneficial effects on the negative symptoms of psychosis (12,25). All five of the newest second-generation antipsychotics, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone have shown statistically significant efficacy as compared to placebo when used as monotherapy to treat acute mania (26). In addition, both olanzapine and aripiprazole have indications for maintenance treatment for bipolar disorder. In studies conducted with hospitalized bipolar I patients
with manic episodes, all of these atypical antipsychotics decreased the components of the manic syndrome in roughly the same percentage when compared to placebo.
with manic episodes, all of these atypical antipsychotics decreased the components of the manic syndrome in roughly the same percentage when compared to placebo.
Olanzapine
Quetiapine
In addition to its effect on bipolar depression as noted later in this chapter, quetiapine has been shown to be effective in the treatment of acute mania both as monotherapy and as combination therapy with mood stabilizers. It has been shown to have equivalent efficacy to lithium after 4 weeks of treatment as monotherapy in doses starting at 300 mg per day moving up to 600 mg per day (29). It has also been useful as an add-on therapy to mood stabilizers (30,31).
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