Keywords: bipolar disorder, drug treatment, mood disorders, mania, schizophrenia, depression mayorLineamientos consensus of experts for the pharmacological treatment of bipolar disorder: a new therapeutic tool


Dr. David A. Kahn, Dr. Gary S. Sachs, Dr. David J. Printz, Prof. Daniel Carpenter,
Dr. John P. Docherty, and Prof. Ruth Ross

 

Introduction
In recent years, the number of treatment options for severe mental illnesses has increased significantly. While this is good news for patients and physicians, it has also been significantly complicated the process of decision making regarding treatment to follow. To help physicians choose the best treatment for each patient individually and in an attempt to improve the quality of service globally, we have seen many efforts both in psychiatry and in other areas of medicine, for create guidelines for clinical treatment. Many of these evidence-based guidelines, such as those derived from the review and evaluation of published research findings (for example, the guidelines of the American Psychiatric Association [APA] for the treatment of major depressive disorder, bipolar disorder 1, 2 and esquizofrenia3). These guidelines review a variety of treatment options and carefully assess the scientific evidence supporting its effectiveness. While these guidelines provide some clinical consensus on the most likely indications of the different treatments, usually fall short on the recommendation of the sequence medicamentos.4 Another problem with evidence-based guidelines is that due to the nature of the investigation clinic is that, in reality, many questions about treatments are not properly focused. There is also a wide gap with the launch of the same, leaving doctors with many unanswered questions about its use. For example, during the last decade, it has documented a significant number of new treatments for bipolar disorder; however, the evidence for these treatments varies widely, including particularly limited in terms of comparisons between treatment and the application sequence data.
Since the number of possible combinations and sequences of treatments available for many diseases, is difficult to establish practical guidelines based entirely on scientific data, 5.6 so expert consensus continues to play an important role in the development of practical guidelines. To fill data gaps between research and important clinical decisions, there have been a significant number of opinion polls of experts, and the results have been used to create practical clinical guidelines for many psychiatric disorders, including schizophrenia, 7, 8 The obsessive-compulsive disorder 9 agitation in dementia, 10 PTSD, 11 and psychiatric problems in delaying mental.12 Original expert consensus guidelines for the treatment of bipolar disorder were published in 1966.13 In 1999, a second survey of new research findings and treatments introduced since the original publication of the guidelines was conducted. The results of this new survey published in April 2000 (copies of the complete guidelines can be downloaded in Adobe Acrobat format www.psychguides.com page. You can also get copies by sending a request including $ 5.00 per copy, for payment Shipping to Admail, 840 Access Road, Stratford, CT 06615). In this article we briefly describe the methodology used in this survey, we summarize the recom-mendations key guidelines clinics, and consider its effectiveness in improving clinical practice and standards of care.
Method consensus of experts to
develop guidelines
Methodology Survey
editors guidelines for bipolar disorders, used a method developed to describe the expert opinion of quantitative and reliable, interviewing experts on bipolar disorder clinics on issues that had not been properly registered or answered categorically in the literature. 14 The questionnaire asked about 48 specific clinical situations in subsections 166, with 1,276 possible intervention options. The survey was sent to 65 US experts in after-around bipolar and leaders in their field, 58 of whom (89%) completed the survey. The experts were identified based on their publications during the 5 years preceding the survey; research grants received from the government or industry, their participation in the publication of the APA: depráctica Guidelines for the treatment of patients with bipolar disorder “(Practice Guidelines for the Treatment of Patients With Bipolar Disorder), 2 and work in other guidelines for mood disorders and section of affective disorders Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Diagnostic and Statistic Manual of Mental Disorders [DSM-IV]). 15 was asked experts to evaluate options in a 9-point scale, adapted dede a format developed by RAND Corporation.16 For a detailed discussion of the methodology and analysis used data readers are advised to refer to the full publication of these lineamientos.17
What valuations mean?
The “first-line treatments” are options that experts usually appropriate for initial treatment in a given situation. The “preferential treatment” is a first-line treatment especially recommended (rated at “9” for at least half of the experts). When choosing between different first-line treatments, or even if you decide to use one, physicians should consider the clinical situation in general, including the patient’s response to treatment in the past, side effects, general medical problems, and preferably
stances of the patient. The “second-line treatments” are
a reasonable choice for patients who can not tolerate or do not respond to first-line options. Alternatively, a second-line option could be used as initial treatment options first line are not suitable for the patient (for example, due to a backlash last, drawback dosage, particularly inconvenient side effects, general medical contraindications, possible drug-drug interaction, or if the experts do not agree on a first-line treatment).
The “third-line treatments” are usually ina-propiados, or used only when recom-gradable alternatives have not been effective.
The results of the survey guidelines
After analyzing the results of the survey and assign grades, unoss easy to use guidelines were developed, organized according to clinical situations (Table 1). In general, the guidelines have two levels of recommendations: (generally corresponding to op-tions classified as first-line) “preferential” options and (usually corresponding to options with high ratings among those second-line) “alternative” options. When more than one choice fell on the same rating level (for example, where several options were classified as
first line) options were ranked according to their average scores.
Recommendations for drug treatment
In this section, we summarize the recommendations of trafficking I lie expert consensus, considering the relationship between opinion and evidence in the key decisions of the experts. (Because the number of potentially useful drugs has made ​​the clinical decision process even more complex, in this survey we only focus on what drugs. Readers can go to the previous edition of the guidelines for bipolares13 conditions as to the recommendations for psychosocial treatment.)
General strategy for the treatment of mania
As shown in Table 2, is initially prefer-ible use a mood stabilizer monotherapy for most types of mania. while for mania with psychosis it is clearly preferred the combination of a mood stabilizer with an antipsychotic. The valuation of preferential treatment represents a particularly strong recommendation. If the patient can not be controlled with monotherapy, after attempting these initial strategies, the physician should add complementary drug – benzodiazepine or an antipsychotic – the choice depends on subclass of mania.
mood stabilizers
for treatment of mania
As shown in Table 3, lithium and divalproex are first recommended treatments for all subclasses of mania line. Divalproex is preferred as tra-preferential treat- for both dysphoric mania combined. These findings are consistent with the resul-states of a prospective large-scale clinical trial comparing divalproex, lithium, and placebo in acute mania 18 and subsequent analysis of the reaction by sub-Carbamazepine is clase.19 the choice between favirecida mood stabilizers, since it is not the only anti-psychotic drug, in well-structured studies have shown effective in the treatment of manía.20 Lamotrigine as initial treatment he described, at best, in the INFE levels Affairs of second-line, reflecting the nature of the evi-cia preliminary efficacy in mania, 21 and perhaps concerns about the need for slow adjustment of the dosage to minimize the risk of skin reactions. Gabapentin was rated mostly as an option for third line, which is consistent with the lack of high quality research, 22 to obtain higher scores on their use for comorbid panic and as a complement to other mood stabilizers.
No much recommended antipsychotic monotherapy except for possible use in psychotic mania. The role of antipsychotics in bipolar disorder are then discussed in
more detail.
Treatment of bipolar depression
Because the lack of data on major depressive disorder in bipolar disorder makes it difficult to investigate this issue, according to evidence-based guidelines in this case is really important to examine the consensus of opinion.
Table 4 summarizes the recommendations on strategies for initial treatment of bipolar depression. For mild depressive bipolar disorder without rapid cycling, only recommend the use of a mood stabilizer. However, for severe depression, recommend adding an antidepressant from the beginning, as well as for psychotic depression would add an antipsychotic or electroconvulsive therapy.
Table 5 provides experts’ recommendations to choose the mood stabilizer for bipolar depression. The first option stabilizer mood stabilizer monotherapy for depression is lithium, along with divalproex (not thoroughly studied for this use) and lamotrigine also listed as first-line drugs, but below lithium. In a controlled, randomized, large clinical trial, lamotrigine is the only drug that has recently been shown to be effective for depression bipolar.23 decades earlier studies have also shown the beneficial effect of lithium.
The choice varies mood stabilizer when it is to be used in combination with an antidepressant. In this case, lamotrigine is not first line while divalproex receives very similar to lithium rating. These results may reflect the preference of the experts use established mood stabilizers to prevent mania induced by antidepressants. Only preferential option, lithium, has been well studied in this situation; in a study of long-term maintenance it was determined that protected against mania when combined with imipramina.24
for spreading depression (an episode of depression that occurs while the patient is on maintenance therapy with lithium or divalproex) experts prefer to first maximize the dose of lithium or divalproex. If monotherapy fails lithium, divalproex, lamotrigine, antidepressants are equally valued as complementary elements, again highlighting the growing role of lamotrigine. There are few research data on which experts can base their recommendations for the election of specific antidepressants for bipolar depression; therefore, their ratings largely reflect clinical experience. Experts give classified as frontline to bupropion, selective inhibitors of serotonin reuptake inhibitors (SSRIs), and venlafaxine, bupropion favoring especially for moderate depression. (All available SSRIs were very comparable rating). The monoamine oxidase inhibitor (MAOI) are a good treatment of reinforcement, having received the same evaluation as nefazodone and mirtazapine. Tricyclic antidepressants are disadvantaged for bipolar depression but had some votes conrespecto weight to more severe depression.
If a patient does not respond to initial treatment with SSRIs experts recommend switching to bupropion (preferential treatment), or instead of, venlafaxine (first line). Bupropion was rated as the antidepressant least likely to cause mania, both in patients undergoing an initial episode, as in those with a history of manic episodes in reaction to other antidepressants. This result is consistent with the fact that the Bupropion is the only antidepressant that has been studied prospectively with this issue in mente.25
If bipolar depression does not respond to initial treatment with the combination of a mood stabilizer and an antidepressant, experts recommend adding lithium to any regime that does not include – especially for a partial reaction step. There were no clear recommendations about other strategies of intensification, although experts seem to suggest the following sequence:
(1) If the patient is not already taken, try an anticonvulsant (divalproex and lamotrigine, then carbamazepine, then gabapentin)
(2 ) Try another antidepressant
(3) Add thyroid hormone (T3 preferable to T4)
(4) Add a stimulant
(5) Add an atypical antipsychotic, clozapine possibly
(6) Use light therapy for seasonal depression
Light therapy for seasonal depression.
Treatment rapid cycling bipolar disorder
Initial preferential treatment that experts recom-mended for both mania to depression in a patient with rapid cycling bipolar disorder is a mood stabilizer (Table 6).
Table 7 shows the Preferred specific recommendations mood stabilizers for fast cycles. Divalproex is preferred for the manic phase of rapid treatment cycle. Carbamazepine is another first-line treatment for all types of mania, lithium remains the first-line option for the euphoric mania. Divalproex monotherapy is the preferred treatment for the depression phase of rapid cycling, while lamotrigine and lithium are equivalent and lower front-line options. Experts recommend adding antidepressants only if mood stabilizers fail.
The strong consensus of the experts regarding treatment for rapid cycling is generally consistent with the results of open studies and retrospective analyzes. These show that divalproex and carbamazepine are superior to litio26,27 – especially in the hobby – and that lamotrigine is more beneficial in depression than mania severa.28 Gabapentin received moderate support for use in rapid cycles. Atypical antipsychotics were favored as an addition to the resistant mania treatment or depression with fast cycles, based only on reports of clinical cases.
Preventive Long-term treatment
to prevent long-term, after a manic episode experts favor the use of lithium or divalproex, or com-combination of both, which has operated during the acute phase of treatment. The effectiveness of lithium in prevention has been established based on data from the 70 (although more recent data indicate a significant failure rate). Confidence in the divalproex reflects the clinical experience; has been more difficult to obtain evidence divalproex controlled maintenance treatment because of the difficulty of including appropriate patients in randomized controlled trials, including placebo.29 But the case reports and open prospective studies show that in some cases, the addition of lithium – even used in triple therapy in combination with lithium and carbamazepine – divalproex can be successful in patients with refractory trastonrnos, including those with cycles rápidos.30,31 Although not asked about using carbamazepine as a preventive treatment, small-scale studies have shown benefits as monotherapy, and in combination with 32 litio.33
dosage and duration of treatment
with standard drugs
When asked about the dose stabilizers Ani-mo, they found standard deviations from 30% to 40% on the recommendations of experts for acute dose of carbamazepine, divalproex and lithium, and about 50% in the dose recommendations for long-term maintenance. Variations in its recommendations were in-even wider for lamotrigine, gabapentin, topiramate and tiagabine. These very wide variations probably reflect the great variability among individuals regarding their metabolism, dose-response requirements and tolerance of side effects. It is emphasized that there was agreement regarding the dose of the deepest agents, which is consistent with the availability of larger amount of experimental data.
If in a week not a reaction of mania is the mood stabilizer, experts consider changing drugs. If after 2 or 3 weeks stabilization achieved partial response, experts introduce another medicine.
When treatment with divalproex mania begins, most experts suggest starting with a full therapeutic dose of 20 mg / [kg. ..día], often defined as a loading dose. Consistent with this approach, experts think they can see results in 1 or 2 days, with divalproex than with mood stabilizers (usually warn wait 1-2 weeks before adding another mood stabilizer). Advise to wait less time to see the reaction to a supplementary antipsychotic and only expect one week or less before trying a second antipsychotic if the patient does not respond to first. Experts are also willing to combine atypical and conventional antipsychotics resistant disorders for treatment, according to clinical practice, although not confirmed experimentally.
Although we do not repeat a question in 1995 on the doses of antidepressants for the acute phase, recommendation of the previous survey was started, and continue with a low dose while at the same time, the goal is the same as for bipolar depression at maximum doses. Both the current and the previous survey, the experts recommended reducing antidepressants after 2-6 months in remission, and not usually recommended 6-12 months.
Atypical antipsychotics
The discussion on the medical treatment of bipolar disorder would not be complete without mention the growing role of atypical antipsychotics in the treatment of bipolar disorder, especially in light of the recent approval by the Food and Drug Administraciórn US (United States Food and Drug Administration [FDA]) for olanzapine hobby and previous approvals of conventional antipsychotics (such as chlorpromazine) for mania. In this survey, the experts evaluated the atypical antipsychotics, except clozapine, as assistant first-line treatment for mania (benzodiazepines and non-psychotic cases (Table 2). The atypical antipsychotics are also rated as first-line agents for the combined treatment of psychotic depression. Furthermore, the current panel rather atypical, as an antipsychotic for long-term maintenance is needed. Atypical were also highly rated as reinforcement at any stage of rapid cycles. Conventional antipsychotics received scores First line only for use in psychotic mania or manic patients who did not respond to testing with 1 or 2 atypical antipsychotics. Conventional antipsychotics long received significant support as second-line treatment for patients with drug inconsistent.
The Survey results are comparable with the data available, including a study showing that olanzapine is more effective than placebo as monotherapy for mania, 34 mounting evidence in favor of risperidone, 35,36 and preliminary experience with quetiapina.37 Recent data also dispelled earlier fears about the common “trigger” by the atypical (although there are isolated cases). Along with the lowest risk of extrapyramidal side effects, this coincides with the recommendations of the experts.
What should be the sequence of atypical antipsychotics for the treatment? First, although experts strongly support the supplemental use of atypical antipsychotics still they have doubts about recommending them instead ánimotradicionales stabilizers monotherapy for mania. Second, as an adjunct to a mood stabilizer medication in hypomania, experts prefer benzodiazepine instead of an antipsychotic. The panel gives the same score to the complementary benzodiazepines or antipsychotics in the treatment of more severe mania without psychotic, and support the use of antipsychotics as essential for psychotic mania. This recommendation, booking antipsychotics for more severe cases, consistent with the
clinical tradition rather than empirical data.
Clozapine was highly qualified for any phase of the treatment of diseases resistant to treatment or rapid cycling. These uses are well supported by studies diseñados.38 Although its use was not approved at the time of this survey, ziprasidone was favorably viewed by the experts that had been used in clinical studies for various disorders. It was also mentioned as a good alternative for patients who had gained weight with other drugs. The role of atypical antipsychotics as complementary treatments and as primary treatments ánimocomo stabilizers in different phases of bipolar disorder is an important area for continuous research.
Possible new mood stabilizers
Following the discovery of the anticonvulsant, divalproex and carbamazepine are effective at least in the manic phase of bipolar disorder, and that seem to be effective in the long-term prevention, investigation of new potential anticonvulsants as mood stabilizers, is now routine. Three anticonvulsants introduced in the United States, in the early to mid 90s, have attracted unusual attention: lamotrigine, gabapentin, and topiramate. In the survey, the only first-line recommendation for a new anticonvulsant was the use of lamotrigine in bipolar depression, either as initial monotherapy or as a good choice to boost lithium or divalproex. As mentioned above, apart from divalproex and carbamazepine, lamotrigine is the only anticonvulsant on which data have been published controlled, multicenter randomized studies, and a large and specific shows, for depression bipolar.23 emphasize that a small randomized pilot study has documented that lamotrigine is
equal to that of lithium in acute mania 39 and an open prospective study in a large sample, it reported having preventive effects mania, hypomania efficacy, and depression, with a 48 weeks longer, mainly when used to enhance the regime existente.21 The preliminary nature of the evidence establishing the role of lamotrigine in mania is reflected in the relatively low rating given to its use.
The rest of anticonvulsant evaluated he received first-line recommendations, but worth mentioning for its growing popularity. Gabapentin is widely used outside epilepsy, anxiety and neuropathic pain, and for mood disorders. Open studies published report their drug use as assistant to accompany other more established treatments, both for use in acute stages and long term for both depression and will appear shortly manía.40-43 negative controlled study on acute mania .44 In the absence of positive findings, it is unlikely that new data controlled for gabapentin are published and, perhaps due to the imminent patent expiry of gabapentin, and the consequent absence of commercial potential, it is doubtful that you make new studies. Experts support use primarily in bipolar patients with comorbid anxiety disorders; in any case only recommended for patients with treatment-resistant disorders,
who have not responded to the most common drugs. We speculate that its acceptance among physicians reflects its recommendation on the treatment of bipolar disorder II (the survey focused more on bipolar I) and its ease of use (no blood, less side effects, low toxic potential). Pregabalin, a related anticonvulsant, not yet available, might deserve more thorough investigation.
There is particular interest in the topiramate for the treatment of mood disorders, because it seems that in some patients who have gained weight with other anticonvulsants, causes weight loss, apparently due to appetite suppression and intensification of metabolismo.45 Three open studies on acute phase suggest that pregabalin is effective in about 50% of patients with mania, but its effects on depression are less claros.46-48 Side, such as kidney stones, peripheral neuropathy, and especially cognitive limitations effects may limit its acceptance. Experts reserved their use for the treatment of mania resistant to treatment. Compared to other anticonvulsants, new data, limited but interesting, indicating that oxcarbazepine, carbamazepine derivative introduced in the United States in 2001 and seems to produce fewer side effects, can be effective for manía.49 The oxcarbazrpina was not available at the time of the survey. In a small pilot, 50 tiagabine, available since 1997 study, seemed to lack effectiveness as a treatment for mania, and the expert panel did not recommend its use. Zonisamide and levetiracetam are two new anticonvulsant whose marketing in the United States began in 2001. No material published on the use of levetiracetam for bipolar disorder, although its easy administration (does not require a slow titration) and the absence of interactions with other drugs, make it a candidate atractivo.51 In a small pilot study has documented the utility of zonisamide for the treatment of manía.52
Electroconvulsive therapy
Despite the availability of several new drugs for bipolar disorder, psychotic depression regarding experts still favor the application of electroconvulsive therapy (ECT), early in the decision process, and prefer to increase the dose of lithium if the initial drugs are not effective. They insist on the application of TEC for non-psychotic depression, if the patient has responded inadequately to treatment with two mood stabilizers, including lithium have proved plus 2 antidepressants. For a patient with a manic episode, which has not responded to lithium and divalproex in addition to antipsychotic, experts gave equal value to the application of TEC and the addition of a third mood stabilizer. On several questions about the rapid cycles and resis-tance to treatment, many experts appointed ECT as its preferred recommendation for acute or maintenance treatment, even when the TEC was not an option offered. These recommendations are consistent with research on depression in manía53 and that ECT is supported.
Conclusion
Do they improve the results guidelines for clinical practice? Given the proliferation of efforts in the last decade to create treatment guidelines, a key question is: These types of tools for the management of treatment do you really produce an overall benefit compared to routine treatments? And if so, what is the cost or savings? It has been shown that there is great variation in the type of care given to patients with conditions psiquiátricas.55 Also, the growing number of new treatments mean that physicians should make an effort to stay informed and upgrade options available to your patients. The use of guidelines and treatment algorithms for clinical practice has been proposed to help improve the overall quality of care, reduce undesirable variations in clinical practice, and provide some guidelines to physicians for water
based on the findings to more investigaciones.56-58 updated the results of studies evaluating the usefulness and effectiveness of clinical practice guidelines have been generally encouraging about the value of such tools to improve health care and resultados.59-65 For example , Grimshaw and Russell59 conducted a meta-analysis of 59 studies on the effectiveness of clinical practice guidelines, and concluded that, in most of these studies, the use of such lineaminetos showed a significant improvement in patient outcomes. The problems related to compliance and dissemination of the guidelines can, of course, reduce their effectiveness, 65-69 having made ​​several proposals on how such tools can be implemented and presented more efficiently (eg algorithms and formal way Tree of decision making, interactive programs computarizados56 4) to make them easier to use and encourage doctors to use more. However, although much more work in this area and the guidelines can not replace a doctor’s judgment is required, it seems that for clinical practice can play an important role in improving the quality of care and outcomes.

References
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2. American Psychiatric Association. Practice guidelines for the treatment of patients With bipolar disorder. Am J Psychiatry. 1994; 151 (suppl 12): 1-36.
3. American Psychiatric Association. Practice guidelines for the treatment of patients With schizophrenia. Am J Psychiatry. 1997; 154 (suppl 4): 1-63.
4. Rush AJ, Crismon ML, Toprac MG, et al. Implementing guidelines and systems of care: Experiences with the Texas Medication Algorithm Project (TMAP). J Psychiatry Behav Health Pract. 1999; 5: 75-86.
5. Djulbegovic B, Hadley T. Evaluating the quality of cl