Un Guia Para Los Pacientes y las Familias
The following participants in the Expert Consensus Survey were identified from several sources: recent research publications and funded grants, the DSM-IV advisers for mood disorders, the Task Force for the APA Practice Guideline for the Treatment of Patients with Bipolar Disorder, and those who have worked on other mood disorder guidelines. Of the 68 experts to whom we sent the bipolar disorder survey, 61 (90%) replied. The recommendations in the guidelines reflect the aggregate opinions of the experts and do not necessarily reflect the opinion of each individual on each question.
| Lori Altshuler, MD University of California, Los Angeles Gregory Asnis, MD Ross Baldessarini, MD James C. Ballenger, MD Mark S. Bauer, MD Charles L. Bowden, MD Joseph R. Calabrese, MD Bernard G. Carroll, MD Dennis S. Charney, MD Bruce M. Cohen, MD William H. Coryell, MD Jonathan Davidson, MD John M. Davis, MD Joseph Deltito, MD Steven C. Dilsaver, MD Steven Dubovsky, MD David L. Dunner, MD Dwight Evans, MD Max Fink, MD Leslie Forman, MD Peter L. Forster, MD Ellen Frank, Ph.D. |
Alan J. Gelenberg, MD Univ. of Arizona Health Sciences Center Robert H. Gerner, MD Robert N. Golden, MD Paul J. Goodnick, MD Jack Gorman, MD John H. Greist, MD Robert M. A. Hirschfeld, MD Philip G. Janicak, MD James W. Jefferson, MD Paul E. Keck, MD Donald F. Klein, MD James H. Kocsis, MD Ranga Krishnan, MD David J. Kupfer, MD Robert H. Lenox, MD Michael Liebowitz, MD J. John Mann, MD Patrick J. McGrath, MD Charles B. Nemeroff, MD Barbara Parry, MD Frederic Petty, MD Harrison Pope, MD |
Robert M. Post, MD National Institute of Mental Health Frederic Quitkin, MD S. Craig Risch, MD Jerrold F. Rosenbaum, MD Norman E. Rosenthal, MD David R. Rubinow, MD A. John Rush, MD Gary Sachs, MD Carl Salzman, MD David A. Solomon, MD Jonathan W. Stewart, MD Peter E. Stokes, MD Andrew L. Stoll, MD Alan C. Swann, MD Michael E. Thase, MD Mauricio Tohen, MD Peter C. Whybrow, MD |
(Bold italics = treatment of choice)
Summary: For patients with classic, euphoric mania, the experts recommend lithium as the treatment of choice, with valproate also a first line choice.1 Valproate is the treatment of choice for mixed episodes, for mania with dysphoric mood, and for mania in a patient with rapid cycling. Carbamazepine is a first line alternative for mixed episodes and for rapid cycling. Lithium is also a first line alternative for mixed episodes.2
| Clinical Features | Euphoric mood or "classic" mania3 | Mixed episode or dysphoric mood4 | Rapid cycling5 |
| Treatment of choice | Lithium | Valproate | Valproate |
| First line: appropriate to use instead of treatment of choice, if preferred based on side effect profile, prior treatment history, etc. | Valproate | Lithium or Carbamazepine |
Carbamazepine |
| Top-tier second line alternatives | Carbamazepine or Lithium + valproate |
Lithium + valproate | Lithium + valproate or Lithium or Lithium + carbamazepine |
Further recommendations: When rapid stabilization is required for severe mania, valproate is the first line choice. Therapeutic blood levels of valproate can be achieved quickly through a loading dose strategy (20 mg/kg/day).6 The Appendix (see p. 40) provides more detailed information on adequate dosing of mood stabilizers.
| Notes: | 1 Question 1 | 3 Questions 1 and 10 | 3 Questions 3 and 10 |
| 2 Questions 2 and 3 | 4 Questions 2 and 10 | 6 Question 9 |
Summary: Mood stabilizers often require several weeks to take effect. During this interim, adjunctive antipsychotics and/or benzodiazepines may be necessary, particularly if the patient has psychotic symptoms, agitation, or insomnia. Moreover, during a manic episode, patients sometimes refuse or cannot safely take mood stabilizers and may initially require treatment with adjunctive medications alone, by mouth or injection. While recommending adjunctive medications, the experts also emphasize the importance of insuring that there is an adequate dose of the mood stabilizer.7
| Clinical features | Mania with psychosis11 | Severe mania without psychosis12 | Hypomania13 |
| Therapeutic goal | Control psychosis Induce sleep and sedation |
Induce sleep and sedation | Induce sleep and sedation |
| First line | Add a high or medium potency antipsychotic to the mood stabilizer. A benzodiazepine may be added to the antipsychotic and mood stabilizer for further sedation. | Add a benzodiazepine to the mood stabilizer. | Add a benzodiazepine to the mood stabilizer. |
| Other alternatives | Switch to a low potency antipsychotic (e.g., chlorpromazine) for added sedation.14 | Add a high or medium potency antipsychotic to the mood stabilizer and benzodiazepine. | Add a high or medium potency antipsychotic. This is rarely needed but sometimes helpful.15 |
| Notes: | 7 Questions 5 and 6 | 10 Questions 5 and 6 | 13 Question 6 |
8 Question 7 |
11 Question 4 |
14 Question 7 |
|
| 9 Question 4 | 12 Question 5 | 15 Questions 6 and 8 |
Editors' note: In patients not responding adequately to the initial treatment plan, clinicians can change the mood stabilizer regimen and/or change the adjunctive medication, or try other treatments. The sequencing or blending of these steps depends on the specifics of the situation and requires clinical judgment. Accordingly, the recommendations are divided into two tables which can be considered in tandem. Table 3A presents the experts' recommendations for subsequent choice of mood stabilizers in treatment-resistant patients. Table 3B presents other alternatives to consider for treatment-resistant patients. We also suggest that clinicians reassess the treatment-resistant patient to insure the accuracy of the diagnosis, to determine whether there are problems with compliance or substance use or abuse, and whether comorbid psychiatric and general medical disorders are present.
(Bold italics = treatment of choice)
Summary: The experts made different recommendations for patients with partial response as opposed to no response to the initial treatment. In patients with a partial response, the usual approach is to add a second mood stabilizer rather than switching medication. In patients with no response, the experts recommend adding or switching to a second mood stabilizer. Valproate is the first line choice to replace or add to lithium, and lithium is the first line choice to replace or add to either valproate or carbamazepine.16
| Initial treatment | Lithium | Valproate | Carbamazepine | |||
| Response | None17 | Partial18 | None19 | Partial20 | None21 | Partial22 |
| Suggested change | Switch to valproate or Add valproate |
Add valproate or Add carbamazepine |
Switch to lithium or Add lithium |
Add Lithium | Switch to lithium or valproate (consider adding lithium) |
Add lithium |
Further recommendations:1. The expert consensus is to change the initial mood stabilizer after 1-3 weeks if the patient is showing no response, and after 2-4 weeks if the patient has shown a partial response.23 These time intervals are measured from the start of treatment and assume there has been rapid titration to adequate doses of the mood stabilizer and adjunctive medication.2. If all the above options fail, the clinician may consider combining valproate and carbamazepine24 or all three mood stabilizers (not rated by experts) with careful attention to drug interaction, or may consider the options described in Table 3B.
| Notes: | 16 Questions 13-18 | 19 Question 17 | 22 Question 14 |
| 17 Question 15 | 20 Question 18 | 23 Questions 11 and 12 | |
| 18 Question 16 | 21 Question 13 | 24 Questions 1-3 and 13-18 |
Editors' note: The following table presents a number of options that can be considered when a patient continues to be treatment resistant despite appropriate changes in the mood stabilizer regimen. Since the sequencing of these is uncertain, clinicians should use their best judgment in deciding when to implement these suggestions. For completeness, we also include several options on which the experts were not surveyed. These added items have no footnotes, but are drawn from the APA Guideline and the literature.
| Option | Comment |
| Change adjunctive medication | Combine benzodiazepine and antipsychotic
if not already tried.25 If need for further sedation on antipsychotic and benzodiazepine, change from a high or medium potency antipsychotic to a low potency agent such as chlorpromazine.26 Consider depot antipsychotic for noncompliant patients. |
| Electroconvulsive therapy (discussed here for mania; see later guidelines for its use in depression) | ECT is an effective anti-manic
treatment. Some experts rated it as first line, although
there was no general consensus on where to place it in
the sequence of treatments.27 Consider strongly for: life-threatening mania; failure of mood stabilizers; or patients who cannot tolerate mood stabilizers or antipsychotics. |
| Using an atypical antipsychotic medication28 | Clozapine is suggested by the experts as
a first line alternative after two failures of
conventional antipsychotics. It is safe to combine
clozapine with lithium and/or valproate, but not with
carbamazepine due to risk of agranulocytosis. Risperidone is a highly rated second line alternative and may be tried if clozapine is contraindicated. However, there are a few reports of hypomania induced by risperidone. The role in bipolar disorder of other new generation antipsychotics awaits further study. |
| Treat antipsychotic-induced extrapyramidal side effects | Akathisia may cause agitation; EPS may cause noncompliance. |
| Calcium channel blockers29 (e.g., verapamil, diltiazem, nifedipine, nimodipine) | The experts had no consensus on the role of calcium channel blockers except for agreement that they are not among the first line drugs. Consider for patients who cannot tolerate other mood stabilizers, or as an add-on to other medications. |
| New anticonvulsant drugs: lamotrigine, gabapentin | Preliminary reports of mood stabilizing properties |
| Notes: | 25 Questions 4-6 | 27 Questions 1-3 | 29 Question 20 |
| 26 Question 7 | 28 Question 19 |
Summary: The acute phase treatment of depression in bipolar I disorder depends on whether psychotic symptoms are present and on the severity of the current depressive episode. In psychotic depression, the recommended treatments are either ECT or the combination of an antipsychotic, a mood stabilizer, and an antidepressant.31 For severe depression without psychotic features, the treatment of choice is the combination of a mood stabilizer and an antidepressant.32 For milder major depressive episodes, an additional first line approach is a mood stabilizer alone.33 There was a clear consensus against using an antidepressant without a mood stabilizer in bipolar I disorder.34 Psychotherapy, added to medication, is a highly rated second line treatment in nonpsychotic patients with bipolar I depression.35 Types of psychotherapy are discussed in Guideline 9.
| Clinical features | Major depressive episode with psychotic features36 | Severe major depressive episode, not psychotic37 | Milder major depressive episode38 |
| First line | ECT or Mood stabilizer + antidepressant+ antipsychotic |
Mood stabilizer + antidepressant | Mood stabilizer + antidepressant or Mood stabilizer alone |
| Second line (only highly rated choices are shown) | Mood stabilizer + antidepressant or Mood stabilizer + antipsychotic |
Add psychotherapy to the mood stabilizer
+ antidepressant or Give ECT |
Add psychotherapy to the medication plan chosen |
| Notes: | 30 Questions 21-23 | 33 Question 23 | 36 Question 21 |
| 31 Question 21 | 34 Questions 21-23 | 37 Question 22 | |
| 32 Question 22 | 35 Questions 21-23 | 38 Question 23 |
(Bold italics = treatment of choice)
Summary: For bipolar II depression, the recommended acute phase treatments are similar to those for bipolar I depression. However, there are two possible differences. First, psychotherapy is rated as somewhat more useful in mild bipolar II depressions than in mild bipolar I depressions. Second, mood stabilizers may sometimes be cautiously omitted in patients who have had minimal hypomania.
| Clinical Features | Major depressive episode with psychotic features40 | Severe major depressive episode, not psychotic41 | Milder major depressive episode42 |
| First line | Mood stabilizer + antidepressant + antipsychotic | Mood stabilizer + antidepressant | Mood stabilizer + antidepressant or Add psychotherapy to the mood stabilizer + antidepressant |
| Second line (only highly rated choices are shown) |
ECT | Add psychotherapy to the mood stabilizer
+ antidepressant to enhance treatment or ECT |
Mood stabilizer alone or Mood stabilizer + psychotherapy |
| Occasionally consider (e.g., if hypomanic episodes are mild and infrequent) |
Omit mood stabilizer; use antidepressant alone or with psychotherapy | Omit mood stabilizer; use antidepressant alone or with psychotherapy |
| Notes: | 39 Questions 24-26, 31, and 38 | 41 Question 25 | |
| 40 Question 24 | 42 Question 26 |
Editors' note: Table 5A presents recommendations for selecting antidepressants for the treatment of bipolar depression. Table 5B gives options for treating insomnia in the context of bipolar depression.
Summary: When using an antidepressant in bipolar disorder, bupropion or a selective serotonin reuptake inhibitor (SSRI) are first line choices.43 The experts also recommend bupropion when the clinician is especially concerned about a manic switch or rapid cycling, while tricyclics are to be avoided.44 If using a mood stabilizer alone for treating depression, the panel recommended lithium as the first line choice.45
| Medication | Comment | |
| First line46 | Bupropion Serotonin reuptake inhibitor |
Bupropion is also recommended for patients likely to switch into mania or rapid cycling.47 |
| Other choices48 | Monoamine oxidase inhibitor | Preferred by research experts as top-tier second line for severe depression |
| Venlafaxine | Preferred over MAOI by many practicing clinicians as top-tier second line* | |
| Nefazodone Tricyclic antidepressants |
Lower-rated among second line No general consensus, except for agreement that these should be avoided in patients with history of antidepressant-induced mania or rapid cycling49 |
|
| First line mood stabilizer, if used alone for depression50 | Lithium | Acute antidepressant effects are often modest. |
Further recommendations: Dosing of antidepressants: As the first line approach, antidepressants are to be used at the same target therapeutic doses, and titrated upward at the same rate, as in non-bipolar major depression ("unipolar depression").51 However, for patients who have histories of being easily switched into mania or hypomania on antidepressants, clinicians may want to use more cautious dosing strategies. See the Appendix (p. 40) for details of dosing.
| Notes: | 43 Questions 27 and 28 | 46 Questions 27 and 28 | 49 Question 29 |
| 44 Question 29 | 47 Question 29 | 50 Question 30 | |
| 45 Question 30 | 48 Questions 27 and 28 | 51 Question 32 | |
| * Results from a survey of 300 practicing clinicians who responded to the same questionnaires (not yet published). | |||
Summary: To treat insomnia in the depressed patient, the first line choice is to add a benzodiazepine to the basic regimen. Highly rated second line alternatives are to rely on the basic regimen, to add trazodone, or to select a sedating antidepressant.52 In nonpsychotic depression, antipsychotics are usually inappropriate for insomnia, but are sometimes used for severe agitation. In contrast, antipsychotics are necessary to treat psychosis when this occurs as part of depression.
| Clinical Situation | Recommendation | Rating |
| Insomnia53 | Add a benzodiazepine to the basic mood stabilizer/antidepressant regimen | First line |
| Rely on the basic regimen alone Add trazodone Use a sedating antidepressant |
Second line | |
| Conventional antipsychotic or risperidone | Third line, rarely needed but sometimes helpful (e.g., for severe agitated depression without psychosis) | |
| Psychotic symptoms in depression54 | High or medium potency conventional antipsychotic in addition to mood stabilizer/antidepressant regimen | First line |
| Notes: | 52 Question 33 | 53 Question 33 | 54 Questions 21 and 24 |
Editor's note: This guideline present recommendations for those patients with bipolar depession who show an inadequate response to the strategies outlined in Gudielines 4 and 5. Table 6A presents recommendations based on the expert survey. Table 6B presents less well-established options.
Summary: The experts suggest the following options for the 30%-50% of patients who do not respond adequately to the initial trial of antidepressant medication.
| Treatment situation | Recommendation |
| Assure an adequate trial of the initial antidepressant55 | Push dose to maximum as recommended for unipolar depression. Duration of trial as in unipolar depression (e.g., 6-12 weeks) |
| No response to initial antidepressant | Trial of an alternate first line
antidepressant (see p. 21)56 Consider MAOI in severe depression.57 |
| Psychotic depression or severe, nonpsychotic depression that has not responded to medication | Strongly consider ECT, especially in psychotic depression.58 |
| Patient has not had lithium | Add lithium to augment current treatment.59 |
| Patient not receiving psychotherapy | Add psychotherapy in mild to moderate depression.60 |
| Patient develops lithium-related hypothyroidism or elevated TSH | Treat with T4.61 |
| Euthyroid patient who has not responded to mood stabilizer alone or mood stabilizer plus antidepressant | Consider augmentation with thyroid
hormone (T3 preferred).62 Replacement dose is preferred; no consensus on high dose.63 |
| Patient has been treated continuously with various antidepressants plus mood stabilizer, but has not had mood stabilizer alone | Try mood stabilizer alone or with thyroid augmentation,64 especially if clinical reassessment suggests subtle rapid cycling (e.g., frequent or chronic depression with brief, subsyndromal hypomanic or mixed periods). Such situations may be aggravated by antidepressants. |
| Notes: | 55 Question 32 | 59 Question 30. Panel members were not asked specifically about lithium augmentation, but rated lithium as somewhat more effective than other mood stabilizers in treating depressive symptoms. | |
| 56 Questions 27 and 28 | 60 Questions 22-26 | 63 Question 35 | |
| 57 Question 47 | 61 Questions 41 and 42 | 64 Question 47 | |
| 58 Question 21 | 62 Question 34 | ||
Summary: For completeness, we include additional options for treating nonresponsive bipolar depression. These approaches were not reviewed by the experts but have been drawn from the APA Guideline, recent literature, and unpublished presentations. Clinicians unfamiliar with these choices may wish to obtain consultation or read published reports before trying to use them in clinical practice.
| Treatment | Comments |
| Combining antidepressants:the first
option is the best established strategy. The use of antidepressant combinations requires that the clinician be experienced and exercise caution. |
Tricyclic + SSRI: watch for elevation of
tricyclic blood levels Bupropion + SSRI, or bupropion plus tricyclic: theoretically may lower seizure threshold Tricyclic + MAOI: add MAOI to TCA or begin together; never add a TCA to ongoing MAOI treatment Caution: do not combine MAOI with SSRI or venlafaxine |
| Carbamazepine or valproate | Sometimes have antidepressant effects alone or added to existing treatment regimen |
| Stimulants | Methylphenidate, d-amphetamine, or pemoline can be used to augment antidepressants; use extreme caution if adding to MAOIs |
| Antipsychotics | Conventional and atypical antipsychotics, especially clozapine, may sometimes have antidepressant effects in nonpsychotic patients. |
| Light therapy | May treat depressed phase of seasonal
bipolar disorder, especially bipolar II disorder, alone
or as an adjunct to antidepressant medication Possibly helpful in nonseasonal bipolar disorder as well |
| Sleep deprivation | May initiate a brief antidepressant
response, which is then maintained by medication Caution: may also sometimes precipitate hypomania or mania |
| New approaches described in preliminary reports | New anticonvulsants may be
antidepressant and mood stabilizing: lamotrigine,
possibly gabapentin Dopamine agonists to augment antidepressants: bromocriptine, pergolide Pindolol: conflicting reports on augmentation of antidepressants |
Editors' note: Guideline 7 deals with medication selection during continuation and maintenance phases and is organized as follows:
Table 7A: Overall medication strategies for continuation and maintenance
Table 7B: Indications for long-term or lifetime prophylaxis with a mood stabilizer
Table 7C: Selecting a mood stabilizer for long-term treatment
Table 7D: Managing selected problems during long-term lithium maintenance
Table 7E: Strategies for treating depression during continuation and maintenance
Table 7F: Strategies for dealing with rapid cycling
Summary: The following general framework was used to ask the panel for its recommendations:
Continuation treatment is the initial period lasting approximately 2-6 months after acute symptoms have resolved. The usual pharmacological procedure in this phase is to continue the mood stabilizer(s) while trying to taper other medications, alert to the possibility of relapse or cycling.
Long-term maintenance follows the continuation period. The goal during maintenance is to prevent new episodes. During maintenance, clinicians must decide how long patients should continue on mood stabilizers, and also evaluate the need for episodic or continual treatment with other antimanic and antidepressant medications based on each patient's pattern of relapse.
| Phase | Definition | Treatment goal | Method |
| Continuation | Approximately the first 2-6 months after
an acute episode has ended. Patients may still have some symptoms and functional problems. |
Prevent relapse of the episode, or cycling into the opposite pole | Adjust dose of mood stabilizer to
balance maximum benefit against side effects. Gradually try to taper other medications (antidepressants, antipsychotics, benzodiazepine). |
| Maintenance | After continuation has ended Patients have stabilized at pre-episode level of functioning and well-being but are vulnerable to new cycles of illness. |
Prevent new episodes Treat recurrences |
Long-term or lifetime prophylaxis with
mood stabilizer Follow acute and treatment-resistant strategies for mania and depression. |
Summary: In bipolar I disorder, long-term or lifetime prophylaxis with a mood stabilizer is the treatment of choice after two manic episodes and should also be considered after one manic episode if it is severe or if there is a family history of bipolar disorder. In bipolar II disorder, prophylaxis may be appropriate after three hypomanic episodes, if there are antidepressant-induced mood elevations, frequent depressions, or a family history of bipolar I disorder.65 We did not ask the experts whether early onset (e.g., before age 20) would be an indication for lifetime prophylaxis after a single episode, a practice advised by some experts.
| Type of disorder | Bipolar I Disorder (Mania)66 | Bipolar II Disorder (Hypomanic, never spontaneously manic)67 |
| Treatment of choice Always recommend prophylaxis . . . |
After two manic episodes |
|
| First line Usually recommend prophylaxis. . . |
After one manic episode if either:
|
|
| Second line Sometimes recommend prophylaxis. . . |
After one unequivocal manic episode |
|
| Notes: | 65 Questions 36 and 37 | 66 Question 36 | 67 Questions 37 and 38 |
Summary: In terms of long-term tolerability, defined as the willingness of patients to stay on medication based on overall side effects, the experts rated valproate and then lithium as first line choices, while carbamazepine was rated as second line. Giving the mood stabilizer in a single h.s. dose may improve compliance. This option is most appropriate with lithium and sometimes with valproate, while there was no consensus concerning carbamazepine.
| Factor influencing selection of mood stabilizer | Selection | Rating |
| Long-term tolerability68 | Valproate Lithium Carbamazepine |
First line First line Second line |
| Suitability for single h.s. dose69 | Lithium Valproate Carbamazepine |
First line Top-tier second line No consensus |
| Notes: | 68 Question 39 | 69 Question 40 |
Editors' note: It is a weakness in our survey that we did not ask the panel to rate the long-term efficacy of different mood stabilizers. We assumed that patients generally continue the same mood stabilizer that they responded to during acute treatment, often at a lower dose in order to minimize side effects. Readers should note that only lithium has been well studied for long-term preventive use.
Summary: The experts had the following suggestions for handling certain serious problems that may occur during maintenance treatment with lithium. Note that this is not meant to be a complete list of side effect management strategies.
| Problem | Options | Rating |
| Lithium maintenance is controlling depression and mania at the lowest possible dose, but patient feels "flat" or cognitively dull70 | Gradually switch to valproate | First line |
| Gradually switch to carbamazepine | Second line | |
| Add thyroid or an antidepressant | No consensus | |
| Do nothing | Inappropriate (i.e., the experts feel clinicians should pay attention to this side effect) | |
| Elevated TSH during successful lithium maintenance; otherwise euthyroid71 | Add T4; continue lithium | First line |
| Clear hypothyroidism during otherwise successful lithium maintenance72 | Add T4; continue lithium | Treatment of choice |
| Gradual onset of mild renal insufficiency (creatinine approaching 1.9 mg/dL)73 | Add a different mood stabilizer and gradually taper lithium | First line |
| Continue lithium at lowest effective dose and monitor renal function | Second line; to be considered when lithium is uniquely effective |
| Notes: | 70 Question 45 | 72 Question 42 | |
| 71 Question 41 | 73 Question 43 |
Summary: Preventing relapse or recurrence of depression in bipolar disorder has not been well researched. In particular, clinicians are often concerned that prolonged use of antidepressants may cause mania or rapid cycling. The experts had no first line recommendations for this problem. The decision for a particular patient must depend on an evaluation of history and medication response.
| Clinical concern | Recommendation | Rating |
| How long should antidepressants be continued after a major depressive episode in bipolar disorder?74 | Taper the antidepressant sooner than one would in unipolar depression (e.g., sooner than 6-12 months) | Top tier second line |
| What strategy should be followed for a patient whose mania is well controlled on lithium alone but who has severe depressive relapses every year or two? (The episodes are not seasonal and the patient is not a rapid cycler.)75 | Some patients do better with
intermittent antidepressants while Others do better if antidepressants are continued indefinitely |
Both options rated top-tier second line; use clinical judgment to decide which best fits an individual patient |
| Add valproate or carbamazepine to
lithium or Add thyroid hormone to lithium |
Second line, sometimes consider |
| Notes: | 74 Question 32 | 75 Question 44 |
Summary: In addition to the mood stabilizer regimen, the experts suggest a number of further strategies for managing rapid cycling during continuation or maintenance, focusing separately on manic and depressive phases.
| Problem | Options | Rating |
| Rapid cycling: selecting a mood stabilizer (extrapolating from acute phase recommendations in Guideline 1) | Valproate | Treatment of choice |
| Carbamazepine | First line | |
| Lithium alone or combined with one of the above | Top-tier second line | |
| Rapid cycling: trouble controlling manic breakthroughs despite multiple mood stabilizers and avoidance of antidepressants76 | Add clozapine or risperidone to mood
stabilizer or Add thyroid hormone to mood stabilizer or Add conventional antipsychotic to mood stabilizer |
Top-tier second line |
| Add calcium channel blocker or Maintenance ECT |
Second line | |
| Rapid cycling: trouble controlling depressive breakthroughs, despite multiple trials of mood stabilizers with antidepressants77 | Add MAOI to mood stabilizer if never tried | First line |
| Stop all antidepressants; use mood stabilizer alone or with thyroid hormone | Top-tier second line-antidepressants can accelerate rapid cycling | |
| Add clozapine to mood stabilizer (experts not surveyed on risperidone) | Second line-at lower end of range | |
| Maintenance ECT | No consensus-some experts favor | |
| Thyroid hormone for rapid cycling: choice and dose in a euthyroid patient | T4 (l-thyroxine) at replacement dose; if not helpful, slowly increase up to 150% of normal free T4 index78, 79 | Top-tier second line |
| T3 (triiodothryonine) at replacement dose; if not helpful, slowly increase up to 150% of normal T3 RIA78, 79 | Lower-tier second line |
| Notes: | 76 Question 46 | 78 Question 48 | |
| 77 Question 47 | 79 Question 49 |
Editors' note: We present the expert panel recommendations in order of decreasing level of care: inpatient care (Table 8A), outpatient crisis interventions (Table 8B), intensive outpatient care (Table 8C), and outpatient treatment during continuation and maintenance (Table 8D).
Summary: Inpatient admission is the treatment setting of choice for patients who are an immediate danger to themselves or others, or who are severely psychotic. The threshold for admission is lower in mania than in depression, probably reflecting the impulsivity and poor insight that are especially characteristic of mania.
| Episode type: | Manic, mixed, or hypomanic episode80 | Major depressive episode81 |
| Treatment of choice | Almost always admit for one of the
following:
|
Almost always admit for one of the
following:
|
| First line | Usually admit for one of the
following:
|
Usually admit for one of the
following:
|
| Second line | Sometimes admit for the following
problems, depending on their number and severity:
|
Sometimes admit for the following
problems, depending on their number and severity:
|
Further recommendations: Estimated length of stay is variable and difficult to predict for individual patients, but usually ranges from 1 to 3 weeks.82 Dangerous ideas or actions, psychosis, and behavior that is disorganized or inappropriate are the most important problems that should improve substantially before the clinician discharges the patient from the hospital.83
| Notes: | 80 Question 50 | 82 Question 52 | |
| 81 Question 51 | 83 Question 53 |
Summary: The expert panel recommends frequent office visits, crisis telephone calls, and intensive outpatient programs as the first line strategy to shorten or avoid hospitalization during the acute phase of care for a manic or depressive episode (but noted that telephone calls are usually not reimbursable, which limits their application). Family visits that include the patient are highly rated second line alternatives. There was no consensus on an option for 23-hour holding beds, a technique that may be too new to assess.84
| First Line | Often useful:
|
| Top-tier second line: | Sometimes useful:
|
Summary: Intensive outpatient programs are intended for several weeks of acute phase care during a manic or depressive episode, either instead of a hospitalization or as a step-down to shorten hospitalization. Frequent medication monitoring is the treatment of choice essential to intensive outpatient programs, supplemented by a variety of psychosocial services that must be more individually tailored.85
| Manic episode or major depressive episode86, 87 | |
| First line: (Treatment of choice) | Always include:
|
| Second line: | Sometimes include, depending on
individual factors:
|
Further recommendations: Though favored by many experts, there was no general consensus on the role of traditional day hospital programs such as 60-90 minute group therapy or ½-day milieu and group activity. The experts were unenthusiastic about full-day programming, unstructured lounge time, and home visits.
| Notes: | 84 Question 54. | 85 Questions 55 and 56 | 87 Question 56 |
| Experts were surveyed for mania only, but interventions may also be helpful in depression. | 86 Question 55 |
Summary: Frequency of visits decreases as patients enter the continuation phase and even more so during the stable maintenance phase. As symptoms stabilize during continuation, the recommendation is a visit for medication management (15-30 minutes) every 1-2 weeks. During the stable maintenance phase, visits may be as infrequent as every 2-3 months. However, severely ill patients need frequent, ongoing medical and psychosocial services.88 Including the spouse or other family during office visits is often useful, especially with more severely ill patients.89 Across all levels of severity, many experts favor combining brief medical visits with non-medically led individual or group therapy, although they did not reach a clear consensus on the optimal frequencies of each type of visit in a blended plan.
| Severity* | Continuation | Maintenance |
| Milder course90
Infrequent episodes;between episodes patient has few symptoms and functions well |
† Medication management (15-30 minutes) with psychiatrist, every 1-4 weeks | † Medication management preferably monthly; every 2-3 months at minimum |
| ‡ Individual or group psychotherapy (45 minutes) in addition to medication management, every 1-2 weeks with non-M.D. or monthly with M.D. | ||
| Moderate course91
Somewhat frequent episodes (e.g., every 2 years); some flare-ups or persistent low-grade symptoms between episodes; some difficulties functioning |
† Medication management weekly or † Psychotherapy and medication management, every 1-2 weeks with psychiatrist |
† Medication management monthly |
| ‡ Individual or group psychotherapy in addition to medication monitoring, every 1-2 weeks with non-M.D. or monthly with M.D. | ||
| Severe course (only one phase,
ongoing care)92 Frequent or continuous episodes (e.g., rapid cycling); frequent, troubling symptoms between full-blown episodes; significant functional impairment |
† Medication management
weekly or † Psychotherapy and medication management every 1-2 weeks with psychiatrist or † Structured psychosocial rehabilitation program including medication management |
|
| ‡
Peer-led clubhouse program ‡ Frequent psychotherapy in addition to medication management: individual or group with non-M.D. |
||
† = recommended for most patients. The experts give a range of first line and top-tier second line ratings that we have condensed into a general recommendation, to be tailored to the needs of each patient.
‡ = consider based on individualized needs. The experts give a range of second line ratings, or give support without reaching consensus, to a range of interventions that should be tailored to the needs of each patient.
*We gratefully acknowledge the suggestions of John Clarkin, Ph.D.
| Notes: | 88 Questions 57, 59, 61 | 90 Question 57 | 92 Question 61 |
| 89 Questions 58, 60, 62 | 91 Question 59 |
Summary: Although medications are necessary in the treatment of bipolar disorder, they are usually not sufficient. Psychosocial interventions are particularly important for improving medication compliance, patient and family education, suicide prevention, psychotherapy for depression (e.g., interpersonal or cognitive/behavioral therapy), and setting limits in mania and hypomania.
| Phase of Illness: | Acute* | Continuation and maintenance93 |
| Most important issues | Monitor closely:
Educate about:
Encourage:
In mania:
|
Inquire about:
Educate about:
Encourage:
|
| Other issues and approaches to consider | Depression:
Mania and depression:
|
Persistent cognitive distortions
related to mood: Long-range issues that may be important to address during maintenance phase when patient is stable:
|
| Notes: | * The experts were not surveyed on psychosocial interventions during acute treatment. The editors thank John Clarkin, Ph.D., for his suggestions. | ||
| 93 Questions 58, 60, 62 | 94 Questions 55 and 56 | ||
Summary: The panel emphasizes communication and psychoeducation: listening to patients' concerns about taking medication and about any side effects they may experience, seeing patients more often if noncompliant, and educating them and their families verbally and with written material.96
| Rating | Recommendation |
| First line, often helpful: |
|
| Second line, sometimes helpful if above not working: |
|
| Notes: | 95 Question 63 | 96 Question 63 |
(Bold italics = assessment of choice)
Summary: The expert panel suggests a more extensive work-up for inpatients than for outpatients.
| Inpatients97 | Outpatients98 | |
| First line tests |
|
|
| Second line tests |
|
Further recommendations:
| Notes: | 97 Question 64 | 99 Question 66 | * Experts not asked; editors' recommendation. |
| 98 Question 65 (the editors elevated CBC and chemistry screen to "assessments of choice") | 100 Question 67 |
Summary: There is no clear agreement among the experts on the recommended frequency of laboratory tests, giving clinicians latitude to exercise clinical judgment.
(Non-bold italics = first line, strongly recommended. Otherwise, choices shown were rated top-tier second line, indicating slightly less support.)
| Lithium101 | Valproate102 | Carbamazepine103 | |
| First 2 months | Serum level every 1-2 weeks | Serum level every 1-2 weeks CBC, LFTs monthly |
Serum level every 1-2 weeks CBC, LFTs monthly |
| Long term | Serum level every 3-6 months Thyroid functions yearly (Total T4, T4 uptake, TSH) Renal functions every 6-12 months (Serum tests for BUN, creatinine, electrolytes) Other: 24-hour urine for volume and GFR only if there is a specific indication; not routinely |
Serum level every 3-6 months CBC, LFTs every 6-12 months |
Serum level every 3-6 months CBC, LFTs every 6 months |
Further recommendations: Levels of mood stabilizers should be obtained whenever there has been a change in dose or clinical situation.*
| Notes: | 101 Question 70 | 103 Question 68 | . |
| 102 Question 69 | * Editors' recommendation |
Summary: To avoid repeated antidepressant-induced manic or hypomanic episodes, the experts recommend covering with a mood stabilizer and using an antidepressant of a different class from the one that caused the mood elevation.
| Condition | Mania or hypomania on antidepressants |
| Recommendation | Mood stabilizer plus antidepressant of a different class |
| Alternative | For hypomania only: mood stabilizer plus the same antidepressant |
Further recommendations: There was less consensus on how to handle patients who have antidepressant-induced activation (e.g., sleeplessness, agitation, or increased energy) that does not meet criteria for mania or hypomania. If such an individual has a strong bipolar family history, it may be advisable to follow the recommendations for antidepressant-induced mania or hypomania given in the table.105
| Notes: | 104 Questions 71 and 72 | 105 Questions 73 and 74 |
(Bold italics = treatment of choice)
Summary: Bipolar disorder is a lifetime illness that continues to require treatment even in patients who have medical complications. The table below indicates which mood stabilizers are least likely to cause problems for patients with specified medical conditions, substance abuse, or who are over age 65. Fortunately, most bipolar patients at risk for medical complications can be managed by selecting an appropriate mood stabilizer and by carefully monitoring the patient's blood levels and medical condition.
| Condition | First line | Top-tier second line |
| CNS structural disease106 | Valproate or carbamazepine | Lithium |
| Liver disease107 | Lithium | |
| Renal disease108 | Valproate or carbamazepine | Valproate + carbamazepine |
| Alcohol misuse109 | Lithium or valproate | Carbamazepine |
| Cocaine use110 | Valproate or lithium | Carbamazepine or valproate + lithium |
| Heart failure* | Valproate | Carbamazepine (but may worsen conduction disease) |
| Persons over age 65, currently in good health111 | Valproate or lithium | Carbamazepine or valproate + lithium |
| Notes: | 106 Question 75 | 108 Question 77 | 110 Question 79 |
| 107 Question 76 | 109 Question 78 | 111 Question 81 | |
| *Because we inadvertently did not ask the expert panel about heart disease, the editors made a recommendation based on the available literature. | |||
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Web site by David Ross, Ross Editorial Services, 4/17/97