Bipolar Support Groups.com blog

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.

Serotonin precursors are compounds used in the production of serotonin, dopamine, and norepinephrine, brain chemicals responsible for mood. A subset of people with bipolar disorder will respond to serotonin precursor treatment, but this intervention is still considered experimental. Both 5-hydorxytryptophan (5-HTP) and S-adenosyl-L-methionine (SAMe, pronounced “Sammy”) are serotonin precursors that can be used in the treatment of bipolar disorder.

5-HTP is a compound made from the amino acid (protein) tryptophan and is primarily found in the brain. 5-HTP is one of the basic building blocks for serotonin, one of the neurotransmitters (brain chemical) responsible for mood regulation. Individuals who experience depression have reduced levels of serotonin in their brains.

Serotonin itself can be manufactured in the laboratory, but when taken as a supplement, it cannot reach the brain (it does not have the ability to cross from general blood circulation into brain circulation, because of a selective membrane that only allows certain chemicals into the brain). 5-HTP came into use in an effort to find a natural way to increase brain serotonin levels. Multiple research studies have demonstrated 5-HTP’s ability to increase serotonin levels when taken as a supplement.

SAMe is a compound produced by the liver and used throughout the body in a chemical process called methylation. Methylation, essential to many chemical reactions in the body, is one of the last steps in the production of the brain chemicals serotonin, dopamine and norepinephrine (which regulate mood).

Because there are no foods that have high SAMe levels, our bodies must make this substance. Our liver usually creates SAMe from the amino acid (protein) methionine, which is found in many foods. Interestingly, supplementing with methionine does not work as well as supplementing with SAMe, because creating SAMe takes multiple steps and requires many co-factors (other nutrients, such as vitamin B12, folate and others) to ensure that the process is successful.

While the use of SAMe in your body is diverse (it participates in over 35 biochemical processes), the process of interest in bipolar disorder is the creation of the brain chemicals mentioned above (dopamine, serotonin and norepinephrine). SAMe slows the breakdown of these brain chemicals, allowing them to work longer. In addition, SAMe speeds production of the receptors which receive these neurotransmitters. The presence of additional receptors allows the neurotransmitters that are present to work more effectively. Some research suggests that SAMe may also make the existing receptors more responsive (better able to receive messages from neurotransmitters). All of these functions combine to create increased levels of neurotransmitters, which can decrease the symptoms of bipolar disorder.

Both 5-HTP and SAMe have a few research studies to support their use as treatment for bipolar disorder. However, no one should use either supplement without consulting with a health care professional because both of these compounds may induce a manic state. They can also interfere with the functioning of standard antidepressant medications and lithium (commonly used to treat bipolar disorder). Again, the use of these supplements should not be attempted without the support of a qualified health care professional.

Safety and Dosing for 5-HTP

A typical dose of 5-HTP is between 150-300 mg a day. 5-HTP should not be used with any other antidepressant medication due to the risk of a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension (high blood pressure), tachycardia (fast heart rate), and other symptoms. As mentioned above, 5-HTP may also interfere with lithium.

Side Effects of 5-HTP

There is a small risk of developing liver toxicity when using 5-HTP. L-tryptophan, a closely related chemical, was pulled from shelves in 1989 when it was associated with liver failure in a few people taking the supplement. While it appears that 5-HTP does not have this problem, it is best to check with your health practitioner before starting any new medication, especially if you currently have (or have a history of) liver problems.

Any substance that increases serotonin carries with it the risk of causing a manic episode. Consult your health care provider before taking 5-HTP.

Safety and Dosing for SAMe

Dosing is typically between 800mg/day and 1600mg/day for SAMe.

Side Effects of SAMe

SAMe is very safe at recommended dosages. Because it is essentially a protein, it has no real side effects other than gastrointestinal upset (see box) and the possibility of causing mania in people with bipolar disorder. Supplementing with SAMe should not be undertaken without the support of your health care provider.

Bipolar disorder (formerly called manic depression) is a mood disorder that causes drastic changes in mood from high manic phases to depressive low phases. The manic phase is characterized by feelings of elated mood and exaggerated self-importance, talkativeness, little need for sleep, increased sociability, racing thoughts, risky or inappropriate behavior, and increased sexual appetite. This period of mania is often followed by a period of depression, with the symptoms mentioned previously (loss of interest or pleasure in previously enjoyable activities; major changes in appetite; sleep problems; fatigue, a feeling of worthlessness or hopelessness; problems with concentration and making decisions; and thoughts of suicide). The change from the manic phase to the depressive phase is called “cycling”. Some people with Bipolar Disorder cycle quickly, while others cycle more slowly. The cycling can be “deep” with very severe manic and very severe depressive phases, or the cycling can be less severe with mild depression and manic phases.

The term “Bipolar Disorder” actually describes four different disorders which range in phase severity and how quickly someone’s mood cycles between phases.

Complementary and Alternative Therapies for Bipolar Disorder

There are no CAM therapies that can take the place of conventional medical therapies for the treatment of bipolar disorder based on current research understandings. Many of the supplements that have been studied for the treatment of bipolar disorder were selected on the basis of how well they treat unipolar or general depression. This is unfortunate, because depression and bipolar disorder are very different diseases which typically require separate interventions.

Even though there are no stand-alone CAM remedies for bipolar disorder, some preliminary studies suggest that many of the supplements suggested below will provide some benefit as adjunctive (complementary) treatments. The most convincing evidence suggests that Omega-3 fatty acids are helpful, but again, this supplement is not recommended as a solo treatment.

The following chart summarizes the common natural treatments for bipolar disorder and the degree of scientific study to support their use:

(A) Well Supported Integrative Therapies for Bipolar Disorder

The only true stand-alone CAM therapy for depression is St. John’s Wort. All other CAM therapies are typically considered adjuncts (additions) to other treatments. The following therapies are currently being studied to determine whether they benefit people with depression. These therapies are generally not harmful, but it unclear whether they are truly helpful. There is some limited research on the effectiveness of these therapies, but study results do not allow us to suggest them as stand-alone treatments for depression.

B-Vitamins

B-vitamins, especially B1 (thiamin), B6 (pyridoxine), B9 (folic acid), and B12 (cobalamin) have all been examined for their contribution to depression. These B-vitamins play many important roles in the body and are necessary to manufacture brain chemicals (GABA, Serotonin, Dopamine, and others) responsible for regulating mood.

Many studies on effectiveness of using B-vitamins for treating depression are promising. However, many more studies must be conducted before concluding that these vitamins are effective in treating all types of depression. Research suggests that the B-vitamins tend to work well for depression related to a deficiency state (such as with alcoholics, or other people with poor nutrition) or for depression associated with premenstrual syndrome.

B-vitamins enhance the effects of many of the standard treatments for depression. Trials of standard antidepressant medications combined with B-vitamins indicated that people recover from depression more rapidly and often with fewer side effects when taking this combination.

The B-vitamins are water-soluble (dissolvable in water) and are easily removed from the body in the urine. They are generally considered safe, with little to no side-effects. However, megadoses (very high doses) of B6 (pyridoxine) have been associated with liver inflammation and nerve damage. It is best to take a multivitamin that contains many B-vitamins (such as a multi-B vitamin combination) or a separate B-complex supplement. Follow the dosing instructions on the vitamin label or consult with your health care practitioner.

Homeopathy

Homeopathy is the use of very small amounts of substances (sometimes an infinitesimal amount of the active ingredient) for the treatment of disease. Homeopathy is based on the principle of analogy; that “like-treats-like”. With this principle in mind, a homeopathic practitioner might give a homeopathic medication that would normally cause a fever to someone who has a fever already. The thought is that the body seeks a “balance” with a disease and if it is pushed further, then the body will push back. If someone who has a fever is “given more fever”, the body will react by reducing the fever.

Homeopathy is very difficult to study due to the varied treatments that practitioners use across different patients. Most homeopathic remedies are individualized to the patient; therefore, 10 patients with depression might get 10 different remedies. While a few studies have shown that homeopathy can be used to treat depression, these studies were not large or well-designed.

The mechanisms by which homeopathy achieves treatment effects is unclear. Many scientists suggest that when homeopathy works, benefits are caused by the so-called placebo effect (patients taking inactive medications show symptom improvement because they think they are receiving active drugs). This has not been established definitively, however. Some clinical trials have shown that homeopathy works better than a placebo (medication without an active ingredient) for treating depression, but other studies have not shown this result. In any event, most homeopathic preparations are so diluted that there is very little chance that an active ingredient (in the conventional sense) is present.

While there are many self-help books on homeopathy, it is best to go to a practitioner and have them personalize a remedy for you. Because homeopathy uses such small amounts of substances, it can be said that homeopathy has no side effects or drug interactions.

Yoga

Similar to exercise, yoga has shown some promise as a treatment for depression. Many yoga practices incorporate deep breathing, stretching, and strengthening exercises along with a mild cardiovascular workout in a class atmosphere.

Yoga is difficult to study in a clinical setting because there are several different factors that can impact its effectiveness. For example, there are many different types of yoga (with varied levels of relaxation or activity), and individual levels of effort during classes may vary. In addition, only certain people are willing to try this form of exercise, so study results may not apply to every group of people who are depressed. There are a few studies that suggest that regular yoga sessions improve depressive symptoms, but their design makes it difficult to draw broad conclusions about the type of person who would benefit most from this therapy.

Yoga can be practiced at home, or you can find a class at a local community/recreation center, gym, or yoga studio. There are forms of yoga that incorporate slow stretching and others that are more active. If you are thinking of trying yoga, visit a class a few times to determine which teacher and style will best meet your needs.

Acupuncture

Acupuncture literally means ‘needle piercing” and is the practice of inserting very fine needles into the skin to stimulate specific anatomic (body) points for therapeutic purposes. In addition to needles, acupuncturists can also use heat, pressure, friction, suction, or electromagnetic energy impulses to stimulate acupuncture points. Treatment is designed to to balance the movement of energy (called qi) in the body to restore health.

Acupuncture has been shown some promise as a treatment for depression. Once again, the varied treatments (how the needles are used) and selection bias (only certain types of people are willing to try acupuncture) affect research trials, making it difficult to determine if acupuncture is helpful for all types of people with with depression. Further study is required.

The specific course and duration of acupuncture treatment depends on the nature and severity of depressive symptoms. A typical course of treatment might involve ten to twelve weekly sessions.

5-hydorxytryptophan (5-HTP) is a compound made from the amino acid (protein) tryptophan and is primarily found in the brain. 5-HTP is one of the basic building blocks for serotonin, a neurotransmitter (brain chemical) thought to be responsible for mood regulation. Individuals who experience depression and anxiety have reduced levels of serotonin in their brains.

Antidepressant medications such as the selective serotonin reuptake inhibitors (SSRI) and monoamine oxidase inhibitors (MAOI) are commonly used to treat depression. These medications work by increasing the total amount of serotonin in the brain or by allowing the serotonin that is already there to work longer.

Serotonin itself can be manufactured in the laboratory, but when taken as a supplement, it cannot reach the brain (it does not have the ability to cross from general blood circulation into brain circulation, because of a selective membrane that only allows certain chemicals into the brain). Multiple research studies support the use of 5-HTP as a natural way to increase brain serotonin levels. Some research has also supported the use of 5-HTP for treating depression, but the studies are based on small groups of people, limiting the conclusions that can be drawn about the potential benefits of 5-HTP for all types of depressed individuals.

Safety and Dosing

A typical dose of 5-HTP is between 150-300 mg a day. 5-HTP must not be used with any other antidepressant medication because of the risk of a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension (high blood pressure), tachycardia (fast heart rate), and other symptoms. 5-HTP also may interfere with lithium (a medication typically used for bipolar disorder).

Side Effects of 5-HTP

There is a small risk of developing liver toxicity when using 5-HTP. L-tryptophan, a closely related chemical, was pulled from shelves in 1989 when it was associated with liver failure in a few people taking the supplement. While it appears that 5-HTP does not cause this problem, it is best to check with your health practitioner before starting any new medication, especially if you currently have (or have a history of) liver problems.

WARNING: Any substance that increases serotonin carries with it the risk of causing a manic episode in people with bipolar disorder (manic depression). A manic episode, the high energy component of bipolar disorder, is characterized by a euphoric (joyful, energetic) mood, hyperactivity, a positive and expansive or agitated outlook on life, a hyper-inflated inflated sense of self-esteem, impulsive and risky behavior, and a reduced need for sleep. While the use of 5-HTP hasn’t been linked to manic episodes, caution is still warranted. Consult your health care provider before taking 5-HTP if you have bipolar disorder.

SAMe (pronounced “Sammy”) stands for S-adenosyl-L-methionine. SAMe is a compound produced by the liver and used throughout the body in a chemical process called methylation. Methylation, essential to many chemical reactions in the body, is one of the last steps in the production of the brain chemicals serotonin, dopamine and norepinephrine (which regulate mood).

Because there are no foods that have high SAMe levels, our bodies must make this substance. Our liver usually creates SAMe from the amino acid (protein) methionine, which is found in many foods. Interestingly, supplementing with methionine does not work as well as supplementing with SAMe, because creating SAMe takes multiple steps and requires many co-factors (other nutrients, such as vitamin B12, folate and others) to ensure that the process is successful.

While the use of SAMe in your body is diverse (it participates in over 35 biochemical processes), the process of interest in depression is the creation of the brain chemicals mentioned above (dopamine, serotonin and norepinephrine). People with depression often have low levels of these brain chemicals, and SAMe affects these neurotransmitters in different ways. SAMe slows the breakdown of these brain chemicals, allowing them to work longer. In addition, SAMe speeds production of the receptors which receive these neurotransmitters. The presence of additional receptors allows the neurotransmitters that are present to work more effectively. Some research suggests that SAMe may also make the existing receptors more responsive (better able to receive messages from neurotransmitters). All of these functions combine to create increased levels of neurotransmitters, which decreases depressive symptoms. Research confirms that both depressed and non-depressed people who supplement with SAMe have higher overall levels of serotonin, dopamine, and norepinephrine. In research on treating depression, the positive effects of SAMe have been impressive. These studies, however, have been small, so it is difficult to determine which groups of people will benefit most from this supplement.

It appears that SAMe works well for people with mild depressive symptoms (with no risk for or indication of suicidal behavior), rather than individuals with more severe major depression. SAMe may also benefit people who cannot take standard antidepressant medications due to their side effects. SAMe could also be used in conjunction with other (standard) anti-depressants, but only under the supervision of a qualified practitioner. Scientists need additional research on SAMe to determine its effectiveness, interactions with other medications, and place within the family of depression therapies.

Safety and Dosing

Dosing for SAMe is typically between 800mg/day and 1600mg/day.

SAMe is very safe at recommended dosages. Because it is essentially a protein, it has no real side effects other than gastrointestinal upset (see box) and the possibility of triggering mania in people with bipolar disorder (see box).

Side Effects of SAMe

SAMe increases the risk of developing a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension, tachycardia (fast heart rate), and other symptoms. Check with your health care provider before incorporating SAMe into your therapy.

WARNING: SAMe has been suspected to cause manic episodes in people with bipolar disorder (manic depression). A manic episode, the high energy component of bipolar disorder, is characterized by a euphoric (joyful, energetic) mood, hyperactivity, a positive, expansive outlook on life, a hyper-inflated sense of self-esteem, impulsive and risky behavior, and a reduced need for sleep. While the number of these cases is low, it is best to avoid SAMe if you suffer from bipolar disorder, or if you aren’t sure if you have bipolar disorder vs. conventional unipolar depression. If you use SAMe, begin treatment only with the support of a licensed health care professional.