Bipolar4LifeSupport

Bipolar disorder causes havoc in patients’ lives. Even in the best of circumstances, successful treatment is challenging. Treatment targets constantly shift; patients are frequently nonadherent; and comorbidity is the rule, not the exception. Diagnosis of bipolar disorder is often difficult. Comorbidities need to be identified and addressed if treatment is to be effective.
The importance of an accurate diagnosis
With apologies to Charles Dickens, bipolar disorder is often experienced as the “best of times and the worst of times.” This polarity often causes bipolar disorder to be undiagnosed, overdiagnosed, or misdiagnosed. Bipolar disorder is associated with a significantly elevated risk of suicide. Moreover, bipolar patients often use highly lethal means for suicide.1 Contributing factors include early age at disease onset, the high number of depressive episodes, comorbid alcohol abuse, a history of antidepressant-induced mania, and traits of hostility and impulsivity.
Bipolar I disorder, with episodes of full-blown mania, is usually easier to diagnose than bipolar II disorder, with episodes of subtler hypomania. Recognizing that the primary mood state may be irritability rather than euphoria increases the likelihood of diagnosis as does the recognition that symptoms often last fewer than the 4 days required for diagnosis by DSM-IV.2 Focusing more on overactivity than mood change further improves diagnostic accuracy, and the use of structured questionnaires is helpful.
Given the greater frequency of depression than manic episodes in bipolar disorder, what clues indicate bipolar disorder rather than unipolar depression? The Table lists factors that may help identify unipolar depression.
A moving target needs moving treatment
Effective personalized treatment recognizes bipolar disorder as a biopsychosocial disorder, but mood-stabilizing medications are the backbone of treatment. These medications fall into 3 categories: lithium, antikindling/antiepileptic agents, and second-generation antipsychotics. The mechanisms of actions by which these medications work are numer-ous and include increasing levels of serotonin, γ-aminobutyric acid, and brain-derived neurotrophic factor (BDNF) and decreasing glutamate levels; modifying dopamine pathways; stabilizing neuronal membranes; decreasing sodium channels; decreasing depolarization; decreasing apoptosis; and increasing neural cell growth/arborization.
Double-blind placebo-controlled studies of the medications—lithium, divalproex, carbamazepine, and atypical antipsychotics—used to treat symptoms of acute mania have demonstrated a response rate of approximately 50% to these drugs. Response was defined as a 50% decrease in symptoms using the Young Mania Rating Scale (YMRS) with onset of response within a few days.
An increasingly intriguing aspect of treatment with lithium and atypical antipsychotics involves their effect on BDNF. In a study of 10 manic patients treated with lithium for 28 days, most (87%) showed an increase in BDNF level (ie, from 406 pg/mL to 511 pg/mL).3
TABLE

Factors that suggest bipolar depression rather than unipolar depression
In a typical 3-week study of acute mania, approximately half of the benefit was seen by day 4. A 3-week, double-blind, inpatient study of olanzapine and risperidone in 274 patients with acute mania found that of 117 patients who had a less than 50% decrease in the YMRS score at 1 week, only 39% responded and 19% had symptom remission at end point. Of 40 patients with a less than 25% decrease in the YMRS score at 1 week, only 25% responded and only 5% had symptom remission at 3 weeks. Of 157 patients who had at least a 50% decrease in the YMRS score at week 1, 84% responded and 64% had symptom remission at 3 weeks.4 Clinically, a medication change should be considered for patients who do not demonstrate substantial benefit by week 1.
A meta-analysis comprising 16,000 patients who had acute mania found that the most effective agents were haloperidol, risperidone, and olanzapine. The least effective were gabapentin, lamotrigine, and topiramate.5
A combination of medications—typically lithium or an antiepileptic with an atypical antipsychotic—is often necessary to successfully treat acute mania. A meta-analysis found the response rate increased from 42% to 62% when an antipsychotic was added.6
Bipolar depression has proved to be more resistant to medication treatment than mania. The same medications are used, with lamotrigine for maintenance treatment. The FDA has approved Seroquel, Seroquel XR, and Symbyax (the combination of olanzapine and fluoxetine), for the acute treatment of bipolar depression. Studies of acute bipolar depression have typically lasted 8 weeks. Approximately half of the benefit oc-curs by week 2, with statistical separation from placebo between weeks 1 and 3.7-9
The best treatment is prevention
Patients who have bipolar disorder almost always require lifelong maintenance treatment, frequently with 2 medications: one to prevent the upside (ie, hypomania/mania), and another to prevent the downside (ie, depression).
Findings from a registration trial showed that lamotrigine more effectively prevented depressions than lithium but lithium prevented mania/hypomania more effectively than lamotrigine.10
Another study added placebo or lamotrigine to lithium treatment for 124 patients. The median time to relapse/recurrence was 3.5 months for those taking lithium monotherapy but 10 months for those who received combination treatment.11
The effectiveness of a combination maintenance regimen was also seen in a study of 628 patients with bipolar I disorder treated for 2 years: 65% of those taking lithium or divalproex alone experienced a recurrence compared with 21% who received quetiapine added to lithium or divalproex.12 However, combination treatment may result in more adverse effects and increased risk of drug-drug interactions.
The best mood stabilizer
The best mood stabilizer for a patient is the one he or she will take. No matter how effective a medication is, it will not relieve symptoms if it is not being taken. The key to effective personalized treatment of bipolar disorder is a good patient-physician connection in which the patient is part of the treatment decision-making process.
Psychotherapy is an integral part of the effective treatment of bipolar disorder, not just an augmentation strategy. Psychotherapies that are helpful include cognitive-behavioral therapy and social rhythm therapy.13 Psychotherapy can focus on several areas, such as education, comorbidities, medication adherence, and interpersonal relationships. In addition, therapy can challenge the automatic, distorted, and dysfunctional thoughts and help the patient maintain social rhythms (eg, consistent sleep). The involvement of family members in treatment enhances success.

Patients may stop taking their medications because the adverse effects become intolerable; they may miss what they perceive as their more satisfying and productive hypomania; and they might believe that a period without symptoms means that they are cured and no longer need medications. One study of 3640 patients with bipolar disorder who made 48,000 physician visits found that 24% of patients were nonadherent (defined as missing at least 25% of doses) 20% of the time. Factors associated with nonadherence included rapid cycling, suicide attempts, earlier onset of illness, anxiety, and alcohol abuse.14

Patients who have bipolar II disorder spend far more time depressed than hypomanic. Lithium appears to be less effective than antikindling agents for rapid cycling as well as for mixed bipolar disorder states.15

Maintenance treatment is necessary for patients with acute mania or acute depression; therefore, choose medications that are more tolerable to the patient to facilitate long-term adherence. Recognize that medications may need to be adjusted or changed—in the acute phase of illness, rapid efficacy is often the priority, while medication adherence is the priority during the maintenance phase.

Other factors to consider when choosing the best medication for a particular patient include:

• A history of treatment response

• A family history of response

• Adverse effects of a particular drug

• Drug interactions

• Pregnancy

• Breast-feeding

Antidepressants

The use of antidepressants in bipolar disorder is controversial because they may induce rapid cycling, especially in patients with episodes of rapid cycling.16 In a study by Altshuler and colleagues,17 patients who had breakthrough depression despite treatment with a mood stabilizer were treated with antidepressants for at least 60 days. Patients who had symptom remission for 6 weeks were followed up for 1 year: 36% of patients who continued antidepressants for longer than 6 months relapsed versus 70% who discontinued antidepressants before 6 months.

A randomized discontinuation study with antidepressants found no statistically significant symptomatic benefit in the long-term treatment of bipolar disorder.18 Trends toward mild benefits, however, were found in patients who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with continuation of modern antidepressants, including SSRIs and SNRIs.

An NIMH study of 159 patients who had breakthrough depression despite receiving a mood stabilizer were treated with sertraline (mean dosage, 192 mg/d), bupropion (mean dosage, 286 mg/d), or venlafaxine (mean dosage, 195 mg/d) for 10 weeks with a 1-year follow-up.19 At the end of 1 year, only 16% of the patients had continued remission while more than 55% had switched to mania/hypomania. The worst results were seen with venlafaxine and the best with bupropion.

In a study by Sachs and colleagues,20 patients who had breakthrough depression despite being treated with mood stabilizers were randomized to paroxetine (mean dosage, 30 mg/d), bupropion (mean dosage, 300 mg/d), or placebo. No significant differences on any effectiveness or safety outcome, including remission rates or affective switch frequency, were found.

Overall, these studies indicate that the role of antidepressants is limited and that, in fact, a trial of a mood stabilizer cannot be considered to have failed unless the failure occurs in the absence of an antidepressant. A meta-analysis of 18 studies with 4105 patients found that combination treatment including a mood stabilizer and an antidepressant was not statistically superior to monotherapy.21

When symptoms persist

Establish the context of each appointment by focusing on changes in occupational, social, family, and health status. Evaluate medication regimens, with a focus on effectiveness for carefully chosen target symptoms and adherence to treatment, as well as medication tolerability and patient attitudes. Be alert to the emergence of early symptoms of mood change, and adjust medications if necessary. Remember that treatment modalities often need to change over time.

Mood stabilizers should be optimized with combination therapy for sustained remission. Antidepressants may worsen the disease course, and a true trial of a mood stabilizer can-not occur within the setting of antidepressants. If symptoms persist, ask: Is the patient taking anything that is making symptoms worse, eg, drugs, alcohol, or antidepressants? Is the patient taking the medications? Is treatment adequate? Is another condition (including subclinical hypothyroidism) interfering with treatment? Is psychotherapy being ignored?

I experienced an interesting confluence of events the other day. My 11-year-old son has been finding out about the great power of online information. Although we limit his access to assistance with homework, he is already a digital whiz kid who knows where to find a great deal of information for writing tomes like Norse history reports. In my day, it would have taken an entire afternoon of digging through texts at a university library to obtain items he found in a few seconds, coluence came about because of what I was doing while sitting next to him. While he was
busy downloading information about Vikings, I was reading an update on a story that I have been following for a few years: the attempt to create a simple, objective blood test that could properly identify mood disorders. That would be a truly handy gadget for mental health professionals to have in their diagnostic tool kits! Going through the literature, which relies heavily on gene expression data, it hit me how profoundly the judicious use of online databases has contributed to the scientific rigor of the research. The Internet was not only seminal to my son’s work but also to this blood test research.

In this column, I will discuss new progress on this Internet-boosted line of inquiry. I will begin with a few basics about differential gene expression and microarrays and will then move on to something that researchers are calling “convergent functional genomics.” As you shall see, the clever use of online databases both confirmed and extended the work done at the bench. As a result, it may very well be possible in the next few years to have a clinic-ready blood test that is capable of diagnosing unipolar and bipolar depression. There may even be a diagnostic test for schizophrenia.

Background

In order to understand this promising research, we first need to review a few facts about differential gene expression, microarrays, and their use in the laboratory. As you may remember, only about 2% of the genome encodes for messenger RNA (mRNA)—sequences usually referred to as class II genes (the rest of the genes encode either ribosomal RNA, called class I genes, or transfer RNA, called class III genes).

You can subdivide class II genes into 2 categories based on the transcriptional activity. Some class II genes are turned on all the time; we often refer to them as “housekeeping” sequences. Some class II genes are expressed quite cell-specifically (a neuron has a very different job description from, say, a gut fibroblast, after all), and they are either completely silent or are called on infrequently, depending on the needs of the cell.

Researchers can capture these “need-specific” class II mRNAs quite easily because of the binding properties of their nucleotides. Consider this example: Suppose you are interested in finding out which neural genes, if any, become activated in the presence of a test medication. You take 2 groups of cells; 1 group will not be exposed to the drug (serving as the unstimulated control), while the other will be exposed to the drug for a set period.

How do you get the medication-specific genes? You simply isolate both sets of mRNA, convert them to helical DNA, and then mix them together. The genes that are commonly expressed in both populations (like those housekeeping genes) will find each other and, with some coaxing, bind together. This makes them double-stranded. The genes that are unique to the medication stimulation have no “partners” and will not bind to anything. This makes them single-stranded.

Since it is easy in the laboratory to separate double-stranded from single-stranded snippets of DNA, we can quickly isolate our “medication-specific” gene population. (This technique can also be used in the opposite direction for some medications, or “turn off” genes.) Simply looking for unpaired populations in the controls can give the researcher valuable information about active and suppressive events related to medication exposure.

Today, populations of nucleotides can be embedded in something we call a “microarray,” which is essentially a plastic tray to which DNA samples have been previously and irreversibly bound. Any DNA can be attached to the microarray, including any (or all) products from the 40,000-plus genes that make up the human genome. Once embedded, you simply wash the plastic with the nucleotide sample that you are testing and see what does and does not bind to the nucleotides on the dish. This hybridization principle was used extensively in the data I am about to describe.

Experimental beginnings

The blood test experiment was an attempt to measure whole genome expression differences in populations with mood disorders (and schizophrenia) using only their blood as the sample substrate. If any unique gene sequences were discovered, would these sequences predict mood disorders in unknown populations? The researchers had their biological work cut out for them. It is quite an experimental leap to ask about events going on in the brain by interrogating only the blood. As you shall see, using a database that looked at human brain–specific gene expression(on the Internet) turned out to be critical for this work.
Le-Niculescu and colleagues1 enrolled 3 cohorts in this study: 2 for depression and 1 for psychotic disor-ders. Twenty-nine patients in the first cohort had been given a diagnosis of bipolar I disorder. The second group, a replicant cohort, consisted of 19 patients with bipolar I disorder. The third group comprised the psychoses-related cohort and included 30 persons with schizoaffective disorders, substanceinduced psychoses, and schizophrenia.

The first task for the researchers was to isolate the genetic substrates of the patients in various phases of their mood disorder. Blood samples were collected when the patients were in a high-mood state (a visual analog scale score of 60 or higher) and in a low-mood state (visual analog scale score of 40 or lower). The various populations of mRNAs were isolated from these blood samples, and the hybridization work involving microarrays began.

Unique gene expression profiles were eventually obtained in both low- and high-mood states and were then divided into forward and reverse mRNA subpopulations.

The forward population represented the manic state. Those mRNA populations were classified as absent in the low (ie, the gene was not expressed in the low-mood state) and present in the high (meaning that the gene was expressed only in the high-mood state). The isolated sequences were considered to be candidate biomarkers for the manic phase of the disorder.

The reverse populations were also isolated. They were absent-in-the-high mood but present-in-the-low mood representatives. These sequences were considered to be candidate biomarkers for the depressive phase of the disorder.

The first category was cross-validation using animal models. This vetting procedure used a pharmacogenomic mouse model for bipolar disorder. Both low-specific and high-specific populations were characterized, and gene sequences were isolated using similar microarray procedures previously deployed in the human work just discussed. In these tests, the source of the mRNAs included not only mouse blood but also brain tissue. The mouse sequences isolated in this fashion were compared with the human sequences previously described.
Next, the strongest gene candidates in each category then underwent an extensive series of tests and cross-checking (Figure). These validation exercises can be divided into 3 categories.

The second category was cross-validation using human postmortem brain sample databases. This vetting procedure involved peering into the Internet and specifically assessing a URL that was carrying data from “GeneCards”—an Online Mendelian Inheritance of Man database (http://www.nslij-genetics.org/search_omim.html). This database contains published reports of changes in the expression of specific genes in postmortem brain tissues that were obtained from patients with bipolar disorder. The idea was to compare the sequences that were isolated from living patient blood samples with sequences that were isolated from the brain samples in deceased patients.

This was a key step because the cross-checking not only involved human-to-human comparisons but it was also the first attempt to establish blood-to-brain connections with the data. As was hinted at previously, the body spends a ridiculous amount of time and resources trying to wall these systems off from each other. Any blood test that is designed to assay something in the brain by looking for something in the blood would need the concordance between the tissues down pat. It is also tricky to determine the phase of illness at which the person died: was it at the low end or at the high end? The researchers assumed that the deaths occurred when the patients were experiencing the low symptoms. Most amazingly, perhaps, the researchers found a number of sequences that converged well with the genes they previously obtained from the blood sample.

The third category was cross-validation using human genetic data linked to mood disorders. This work also involved extensive use of an Internet-borne database. An online sequence-based integrated map of the human genome is published by the University of Southampton in the United Kingdom. (There is a similar collection of information called the Marshfield Clinic Research Foundation database in the United States.) These databases on gene sequences include previously published works shown to have a genetic linkage to mood disorders.

Taken together, 3 separate vetting procedures were used to screen the sequences isolated from the original living human cohorts. At each step, a single question was asked: “Do any of the sequences match?” Answering this question was not straightforward, and statistical analyses were then performed to determine convergence. The researchers termed the entire protocol “convergent functional genomics.”

That any genes could still be present after such screening is a testament to both the rigor of the work and the insightful nature of the experimental design. The researchers did indeed find matches. A total of 10 candidate genes survived the screenings. Five came from the selection in the high-mood, or manic population: Atxn1, EdnRb, Edg2, Fzd3, and Mbp. Five came from the selection in the low-mood, or depressive population: Erbb3, FGfr1, Mag, Pmp22, and Ugt8.

What do these gene sequences do? This is probably the most biologically interesting aspect of the work, and it is easily the most opaque. Some of the gene sequences are involved in the normal myelination of neurons. These included the sequences Edg2, Mag, Mbp, Pmp22, and Ugt8. Several of these are involved in growth factor signaling: Erbb3, FGfr1, Fzd3, Igfbp6, and Ptprm.

What does the isolation of these sequences mean to our biological understanding of mood disorders? Not much, unfortunately. Growth factor and signal transduction sequences seem to hold the greatest promise for obtaining early leads. The presence of so many myelination-specific genes in an affective disorder, however, is less intuitive and certainly more surprising, and their roles are nearly a complete mystery.

Discovering biological roles was not the point of this work, however. There was a more practical issue: Given the blood data, how well did these sequences actually predict a mood disorder?

The answer makes these data especially compelling for the future clinic. Using the original populations, these 10 biomarkers were tasked to predict which patients had what disorder and which phase they were experiencing at the time of the test.

Such prediction is relatively easy. The researchers calculated a score on the basis of the ratio of high-mood to low-mood genes, using both sensitivity scores and specificity inventories. Their results were a stunner. In the first cohort (high mood only), sensitivity was 84.6% and specificity was 68.8%. In the second cohort (high mood only), sensitivity was 70.0% and specificity was 66.7%.

Similar results were obtained when predicting low mood. In the first cohort (low mood only), sensitivity was 76.9% and specificity was 81.3%. In the second cohort (low mood only), sensitivity was 66.7% and specificity was 61.5%.

These are extraordinary figures. As the researchers themselves pointed out, these scores are comparable to results obtained in prenatal tests that can predict Down syndrome. They do indeed seem to have uncovered a working blood test for an affective disorder.

Conclusion

These data were obtained with adults who were experiencing a specific disorder in an even more specific phase. The test was conducted with an assay that could be administered in any clinic capable of drawing someone’s blood. Although not mentioned in this space, similar results were obtained in predicting disease states in the psychoses cohort. Some believe
that blood test kits that are capable of such diagnostic discrimination could be available in as few as 5 years.
Of course, the robustness of these findings immediately suggests the commissioning of larger, more prospective studies. It also suggests something equally extraordinary: the critical role of the creation of specific databases and how their unfettered, online access took part in uncovering such big science.

ABILIFY:

Generic name
Aripiprazole

Antipsychotic second generation

Indications
Schizophrenia, Bipolar Disorder

Dosage forms
2mg, 5 mg, 10mg, 15mg, 20mg, 30 mg

Maximum daily dose
Adults 30 mg
Children 30 mg 10-17 yrs old

Half life

75 Hours

Side effects

Nausea, drowsiness, muscle stiffness, restlessness, shakiness, constipation, cold symptoms, upper respiratory infection, muscle weakness, rash, dizziness, fainting, seizures, sexual problems, elevated blood sugar, abnormal muscle movements, weight gain,

There may be more side effects than listed here!!!!

NOTE:

Always contact your doctor about any unusual side effects you may experience!!!!

ADDERALL

GENERIC NAME:
Dextroamphetamine, Amphetamine.

Brand Name: Adderall

CLASS:
Psychostimulant

Indications:
Attention deficit Disorder, Narcolepsy

Dosage forms:
5 mg, 7.5 mg, 10 mg, 12.5 mg, 20 mg, 30 mg

Maximum daily Dosage

ADULTS 60 mg
CHILDREN 40 mg

HALF LIFE

10-12 hours

Side effects:

Loss of appetite, trouble sleeping, nervousness, abdominal pain, weight loss, rpaid heart beat, nausea, rash, head ache, rash, drowsiness, blurred vision, worse psychotic symptoms, motor tic, seizure, abnormal heart beat, hair loss, increase eye pressure

This is not a complete list check with your doctor for other symptoms you may experience…

ALPRAZOLAM

Brand name
Xanax

Class
Benzodiazepine

Indications

General anxiety disorder, panic disorder

Dosage forms

0.25 mg, 0.5 mg, 1 mg, 2 mg

Maximum daily dosage
Adults 4 mg
Children Non-FDA approved

Half life 12-15 hours

Side effects

dizziness, drowsiness, nausea, headache, sexual problems, weakness, confusion, liver problems

This is not a complete list check with your doctor and report any unusual side effects

AMBIEN

Generic Name
Zolpidem

Class
Non-benzodiazepine  hypnotic

Indication
Insomnia

Dosage
5 mg, 10 mg

Maximum Daily Dosage
Adults 10 mg
Children NON-FDA approved

Half Life
2.5 hours

Side effects

Head ache, drowsiness, diarrhea, dizziness, lethargy, drugged feelings, palpitations, constipation, rash

This may not be a complete list of side effects always check with your doctor!!

According to DSM-IV diagnostic criteria, bipolar disorder (bipolar affective disorder, manic-depressive disorder) is characterized by marked mood swings between mania (mood elevation) and depression. The essential feature of bipolar I disorder (BDI) is a clinical course that is defined by the occurrence of 1 or more manic or mixed episodes; the essential feature of bipolar II disorder (BDII) is a clinical course that is defined by the occurrence of 1 or more major depressive episodes accompanied by at least 1 hypomanic episode. As such, bipolar disorder can cause significant personal distress and social dysfunction.

Bipolar disorder has been subdivided in several ways, but classically there are 2 clinical categories of the disorder. BDI is characterized by the occurrence of 1 or more manic or mixed episodes (mixed episode means that symptoms of mania and depression are present at the same time). Often individuals with BDI have also had 1 or more major depressive episodes. Episodes of substance-induced mood disorder (caused by the direct effects of a medication, other somatic treatments for depression, drug abuse, or toxin exposure) or of mood disorder caused by a general medical condition are not considered when making a diagnosis of bipolar disorder. By contrast, BDII is diagnosed when depression is interspersed with less severe episodes of elevated mood that do not lead to dysfunction or disability (hypomania).

Although individuals with BDI can return to a fully functional level between episodes, some continue to display mood lability and interpersonal or occupational difficulties. Manic symptoms are the hallmark of the illness and can represent a real medical emergency. However, bipolar depression is often much more clinically significant.1
Depression was the third leading cause of burden among all diseases in 2002, and it is expected to rise in the next 20 years.2 Evidence suggests that depressive episodes and symptoms are equal to or more disabling than corresponding levels of manic or hypomanic symptoms and that only subsyndromal depressive symptoms (and not subsyndromal manic or hypomanic symptoms) are associated with significant impairment in patients with bipolar disorder.3 This scenario highlights the need for effectively treating bipolar depression.

Although antidepressant drugs remain the mainstay of treatment for unipolar major depression in both primary and secondary care settings,4 the evidence to support antidepressant treatment for bipolar depression is limited and increasingly controversial—especially now that evidence is available for alternative medications, including quetiapine and lamotrigine.5
Apart from the limited evidence, a key problem with antidepressants is the potential for increasing the risk of iatrogenic episodes of elevated mood. This is the reason many reviews and guidelines for bipolar depression have recommended the use of a mood stabilizer (usually lithium or valproate) rather than an antidepressant as the first-line treatment for bipolar depression.6,7 Antidepressants are advised only as second-line treatment and always with a concurrent mood stabilizer to prevent switching to mania. However, in real-world clinical practice, antidepressants are still frequently prescribed for bipolar disorder.8 Thus, 3 important clinical questions arise: (1) What is the effectiveness (if any) of antidepressants in bipolar depression? (2) What is the risk of manic switching? (3) How effective are antidepressants in preventing relapse of bipolar depression?

Efficacy of antidepressants and risk of manic switching

In 2004, the efficacy and safety of antidepressants for the short-term treatment of bipolar depression were studied and the results were analyzed.9 The main aims of the study were to shed light on the effectiveness of antidepressants using a methodologically sound approach, to quantify the increased risk of a manic switch, and to see whether there were antidepressants that were more effective or less likely to produce a switch. Using various electronic databases, the authors performed a systematic review and meta-analysis of randomized controlled trials.
Twelve studies were included and 1088 participants were analyzed. Participants were adults aged up to 70 years of whom approximately 60% to 70% were women; patients with a diagnosis of serious physical illness or substance abuse were excluded. The review found that antidepressants significantly increased treatment response at 4 to 10 weeks. Comparing 1 or more antidepressants with placebo, patients taking an antidepressant (paroxetine, imipramine, fluoxetine, tranylcypromine, or selegiline) were more likely to respond (risk ratio [RR], 1.9; 95% confidence interval [CI], 1.5 to 2.3). The number needed to treat (NNT) with antidepressants was 5 (95% CI, 4 to 7). (The NNT is a measure of treatment effectiveness and the average number of people who need to be treated with a specific intervention [for a given period] to achieve 1 additional beneficial outcome.)

There were fewer data available for analysis of remission, but the results were consistent. Patients treated with an antidepressant (paroxetine, imipramine, or fluoxetine) were more likely to achieve remission than those who were not taking an antidepressant (RR, 1.41; 95% CI, 1.11 to 1.80). NNT was 9 (95% CI, 5 to 33). In the studies comparing antidepressants with placebo, about 75% of patients received a concurrent mood stabilizer or an atypical antipsychotic (this point should be taken into account in order to draw clinically meaningful conclusions).
The review data did not suggest that switching to mania is a common early complication of treatment with antidepressants. In the review by Gijsman and colleagues,9 there was no evidence of an increased risk for switching to a manic episode in the included trials. The event rate for antidepressants was 3.8% and for placebo it was 4.7%. This difference was not statistically significant. Gijsman and colleagues9 also looked at whether some antidepressants are less likely to produce a manic switch. They found 3 trials that allowed comparison between 2 important classes of antidepressants, tri-cyclic antidepressants (TCAs), and SSRIs. Findings from this study show that switching occurred in 8% of patients taking TCAs versus 0% of those taking SSRIs (although the difference is not statistically significant), and suggest that TCAs may be more likely to induce mania than SSRIs.9 The main limitation of these analyses is that there were few manic events overall, limiting the power to detect a clinically important difference between compounds.

Recently, Sachs and colleagues10 reported the results of a large (N = 366) randomized trial comparing mood stabilizers alone (valproate, lithium, carbamazepine) with combination therapy with an antidepressant (paroxetine or bupropion) plus a mood stabilizer in patients with bipolar depression. At 26 weeks, there was no significant difference in the proportion of patients who achieved a durable recovery (27.3% vs 23.5% respectively), nor was there any difference in the pro-portion of patients who experienced a manic episode (10.7% vs 10.1%).

Other studies have examined the relative risk of switching into hypomania or mania associated with second-generation antidepressants in patients with bipolar depression.11-13 Results conflicted somewhat with the findings reported by Gijsman and colleagues.9 Examining the comparative risks of switching into hypomania/ mania during acute and continuation trials of adjunctive antidepressant treatment for bipolar depression, one study found that adjunctive treatment with antidepressants for bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania even during short-term treatment.13

This 10-week trial examined the relative acute effects of 3 second-generation antidepressants (bupropion, sertraline, and venlafaxine) as add-on treatments to mood stabilizers. In this study, 174 outpatients with BDI or BDII (stratified for rapid cycling) and in the depressed phase were randomly treated with a flexible therapeutic dose of an antidepressant. All 3 antidepressants were associated with a similar range of acute response (49% to 53%) and remission (34% to 41%); how-ever, a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline was found: standardized rating scale scores showed that switching occurred in 10% of patients taking bupropion, 9% taking sertraline, and 29% taking venlafaxine.

Interestingly, this trial also found a strong interaction between the rapid-cycling status of patients and the relative risk of switching for all 3 medication groups. In participants without rapid cycling disorder, the risk of switching was identical for all 3 medication groups. It could be that the dual actions of venlafaxine on serotonin and noradrenaline reuptake, which may account for its greater efficacy in patients with unipolar depression,14,15 may have contributed to the higher rate of switching with this agent than with the other 2 agents. These findings may also be consistent with the higher switch rates for the TCAs, which represent combined serotonin and noradrenaline reuptake inhibitors.9

The results from the study by Post and colleagues11 were confirmed in a long-term continuation treatment follow-up phase lasting up to 1 year.13 Hence, more caution appears indicated for patients with bipolar depression for use of venlafaxine than use of bupropion or sertraline as adjunctive treatment to a mood stabilizer, especially if there is a history of rapid cycling. It should be noted that all of these antidepressants are FDA-approved for the treatment of major depression but are not FDA-approved for use in bipolar depression.

Effect of antidepressants in preventing relapse

The other compelling clinical issue in bipolar depression is the risk of recurrence and prevention of relapse. Bipolar disorder is known to be a recurrent disorder, and more than 90% of patients with bipolar disorder experience recurrences.16
However, available data are scarce on the clinical features associated with the risk of recurrence. Interesting findings resulted from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a national longitudinal public health initiative funded by NIMH.17 One of the main aims of the trial was to look for the features associated with risk of recurrence.18 The study prospectively enrolled patients with bipolar disorder who were receiving treatment according to contemporary practice guidelines and observed them for up to 24 months.
Of the 1469 participants who were symptomatic at study entry, 858 subsequently achieved recovery (58.4%). During the 24-month follow-up period, 48.5% of patients experienced recurrences, and depressive episodes developed in more than 34.7%, compared with manic/hypomanic/mixed episodes in 13.8%. Furthermore, in this study, residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence.
Unfortunately, we found just one systematic review investigating the effectiveness of long-term use of antidepressants, which did not provide sufficient evidence to assess the ability of antidepressants to prevent relapse of bipolar disorder.19 The review found 7 randomized controlled trials that enrolled 363 people with BDI or BDII. Data were found only for imipramine, desipramine, bupropion, and fluoxetine (antidepressants) and lithium (a mood stabilizer).
The review provided a narrative overview of the studies, because the variety of comparisons did not allow researchers to perform a meta-analysis or to quantify reliable conclusions. The available evidence suggested that there was no clear benefit for routinely adding long-term antidepressants to ongoing treatment with lithium. Moreover, the same review found that antidepressants may be less effective in preventing relapse when they are prescribed without a mood stabilizer (in this case, lithium).19

Clinical implications
There is some evidence20 that antidepressants are effective in the short-term treatment of bipolar depression, but a large recent trial reported no benefit10 and caution should be paid to the risk of manic switching. Alternative agents, such as quetiapine or lamotrigine, should be considered. When using an antidepressant, it may be prudent to use an SSRI or bupropion rather than a TCA or venlafaxine as first-line treatment. However, the patient history (ie, response to antidepressant treatment without adverse effects, including treatment-emerging manic switch) should be the best guide for choosing the individual treatment strategy.
Looking at the randomized evidence, there is no support for the addition of long-term antidepressants to ongoing treatment with a mood stabilizer for maintenance treatment in persons with bipolar depression. Early discontinuation following resolution of the acute episode should be con-sidered. Recurrence is frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce the risk of recurrence. Given the limited evidence, there is a compelling need for further studies with longer follow-up and careful definition of the risk/ benefit profile in terms of efficacy and tolerability.

Recent evidence found conflicting results about possible correlates between suicidality and antidepressant exposure.21,22 This aspect is of crucial importance when using antidepressants not only for bipolar disorder but also for unipolar disorder,23 and it indicates important directions for further research. New pharmacological strategies with agents different from antidepressants are under investigation (quetiapine, lamotrigine, olanzapine, olanzapine plus fluoxetine) and need to be carefully evaluated to improve our therapeutic skills for treating bipolar depression.