Chapter 3
Bipolar Disorder

The Web site for NAMI, the National Alliance for Mental Illness, at www.nami.org, describes bipolar disorder as follows:
What is Bipolar Disorder?
Bipolar Disorder, or manic depression, is a serious brain disorder that causes extreme shifts in mood, energy, and functioning. It affects 2.3 million adult Americans, which is about 1.2 percent of the population, and can run in families. The disorder affects men and women equally. Bipolar Disorder is characterized by episodes of mania and depression that can last from days to months. Bipolar Disorder is a chronic and generally life-long condition with recurring episodes that often begin in adolescence or early adulthood, and occasionally even in children. It generally requires lifelong treatment, and recovery between episodes is often poor. Generally, those who suffer from Bipolar Disorder have symptoms of both mania and depression (sometimes at the same time).

What are the symptoms of mania?
Mania is the word that describes the activated phase of Bipolar Disorder. The symptoms of mania may include:

What are the symptoms of depression?
Depression is the other phase of Bipolar Disorder. The symptoms of depression may include:

What is a "mixed" state?
A mixed state is when symptoms of mania and depression occur at the same time. During a mixed state depressed mood accompanies manic activation.

What is rapid cycling?
Sometimes individuals may experience an increased frequency of episodes. When four or more episodes of illness occur within a 12-month period, the individual is said to have Bipolar Disorder with rapid cycling. Rapid cycling is more common in women.
The category of bipolar disorder breaks down into a few sub-categories. The University of Maryland Medical Center Web site (www.umm.edu/patiented/index) has this to say about the varieties:

Bipolar Disorder Categories
Bipolar disorder is classified according to symptom severity as bipolar disorder I, bipolar disorder II, and cyclothymic disorder. Some experts believe these are actually separate disorders with different biologic factors accounting for their differences.
Bipolar Disorder Type I. Bipolar disorder type I is characterized by at least one manic episode, with or without major depression. With mania, either euphoria or irritability may mark the phase, and there are significant negative effects (such as sexual recklessness, excessive impulse shopping, sudden traveling) on a patients' social life, work, or both. Untreated mania lasts at least a week or results in hospitalization. Typically, depressive episodes tend to last six to 12 months if untreated. However, untreated manic episodes last three to six months.
Hypomania and Bipolar Disorder Type II. Bipolar disorder type II is characterized by at least one episode of hypomania and at least one episode of major depression. With hypomania the symptoms of mania (euphoria or irritability) appear in milder forms and are of shorter duration. Bipolar II depression is the most commonly expressed form of all bipolar disorders and it is also highly associated with suicide risk.
Cyclothymic Disorder. Cyclothymic disorder is not as severe as either bipolar disorder II or I, but the condition is more chronic. The disorder lasts at least two years, with single episodes persisting for more than two months. Cyclothymic disorder may be a precursor to full-blown bipolar disorder in some people or it may continue as a low-grade chronic condition.

Course of the Illness
Bipolar disorder can be severe and long-term, or it can be mild with infrequent episodes. The usual pattern of bipolar disorder is one of increasing intensity and duration of symptoms that progresses slowly over many years. (Patients with the disease, however, may experience symptoms in very different ways.) A bipolar disorder patient averages 8 to 10 manic or depressive episodes over a lifetime, but some people experience more and some fewer episodes.
Typical Bipolar Cycles.
In most cases of bipolar disorder, the depressive phases far outnumber manic phases, and the cycles of mania and depression are neither regular nor predictable. Many patients, in fact, experience mixed mania, or a mixed state, in which both mania and depression occur.
Rapid Cycling.
About 15% of patients have a temporary, complicated phase known as rapid cycling, in which the manic and depressive episodes alternate at least four times a year and, in severe cases, can even progress to several cycles a day. (Some experts suggest that rapid cycling may first occur in bipolar disorder patients who are on antidepressants, which trigger a switch to mania and set up a cyclical pattern.)
Additional types of bipolar disorder are under consideration, but are not yet considered standard diagnostic categories. These additional types include
Bipolar Disorder Type III.
Bipolar disorder Type III refers to manic or hypomanic episodes induced by antidepressant medication. This situation can arise when someone who has bipolar disorder is diagnosed with depression and given an SSRI, or other serotonergic medication, without an accompanying mood stabilizer.
Bipolar Disorder Type IV.
Bipolar disorder Type IV refers to a condition characterized by the late development of depression in an individual of lifelong "hyperthymic" temperament, meaning someone who has shown hypomanic traits on a steady, as opposed to episodic, basis.
Psychotic episodes can also be a symptom of bipolar disorder. The presence of psychosis makes diagnosis more difficult, as the illness can easily be confused with schizophrenia.
This chapter will refer to normal depression as unipolar depression, to distinguish it from the depressive episodes of bipolar disorder. While unipolar depression is bad enough, people with bipolar disorder have twice the number of undesirable, and uncontrollable, moods, as well as no control over the transition between them. Thus it it is not surprising bipolar disorder is more difficult to treat than unipolar depression.

3.1  Causes of Bipolar Disorder

The cause of bipolar disorder remains unknown. It seems clear that the disorder involves brain chemistry at some level, and possibly neurological problems, especially given the utility of some anti-seizure medications in treatment. It also seems clear that, as for Major Depressive Disorder, bipolar disorder is partly inherent in the brain, and partly a response to external circumstances.
The principal hypothesis for bipolar disorder is the "Kindling Model." This model was first developed in the context of seizure disorders (specifically epilepsy), where it was discovered that repeated electrical stimulation of the brain in rats, at levels too low to cause seizures initially, nevertheless resulted in seizures developing after a couple of weeks. The rats' brains had become sensitized to this stimulation in a way that resulted in seizures from levels of stimulation that had formerly been too low to cause them. (It was found that similar results were producible through chemical stimulation, as well.)
The term "kindling" was selected because the process seemed analogous to lighting a fire (burning a big log) by lighting lots of little fires first (small pieces of kindling wood).
The kindling hypothesis has some implications.
These implications are observed in clinical practice.

3.2  The Role of Gamma-Aminobutyric Acid (GABA)

One neurotransmitter that does appear to play a major role in both seizure activity and bipolar depression (particularly the manic phase) is gamma-aminobutyric acid (GABA), which is described in Section  1.3.2.
Receptors for GABA come in three varieties: GABA-A, GABA-B, and GABA-C. The Gabitril Web site (www.gabitril.com/physicians/gaba/default.asp) has this to say about GABA:
G-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system (CNS) and is widely distributed throughout the brain. Approximately 60-75% of all synapses in the CNS are GABAergic.
The Role of GABA in CNS
GABA binds to three principal receptors, each of which is involved in different physiologic functions:
Enhancing GABA Activity
GABAergic activity may be enhanced by either:
GATs are membrane-transporter proteins that remove GABA from the synaptic cleft.
Four distinct GATs have been identified: GAT-1, GAT-2, GAT-3, and BGT-1; they are located on neurons, both pre- and postsynaptically, and on glial cells. They differ in CNS distribution and localization.
Finally, medications that increase GABA concentration or effectiveness tend to cause sleepiness, and benzodiazepines (which enhance GABA activity) are occasionally prescribed as sleep medication for occasional insomnia (see Section 3.9). GABA reuptake inhibitors may also promote sleepiness. It may be that the increase in GABA activity or concentration, which produces sleepiness in many individuals, acts primarily to counter mania (without sleepiness) in those who have bipolar disorder,

3.3  Treatments for Bipolar Disorder

Bipolar disorder requires medical treatment. Therapy alone cannot address the underlying causes, which are neurological in origin. This is in contrast to the case of unipolar depression, as some instances of the latter arise purely from factors within the capability of the individual to change, often with help from a therapist. However, therapy does have a role to play in the overall management of bipolar disorder. A good therapist can help a patient develop improved coping strategies for dealing with the illness. This is more important than it might sound, as the nature of bipolar disorder (particularly manic states) can severely distort the patient's capacity for judgment, and a therapist's input is therefore of particular value. For this reason, therapy is recommended as part of the approach for treating bipolar disorder, at least until the patient and therapist agree that the patient is stabilized and doing well.
The only technique, other than medication, that has been found to be effective in treating bipolar disorder is that of electroconvulsive therapy, or ECT. This technique, which is described in Section 1.7.2, deserves careful consideration. Because of its drawbacks, ECT is not the method of choice for treating bipolar disorder; however, it is effective, and worth considering if medication has failed.
The experimental treatments described in Section 1.8 may be of interest as well, although their effectiveness for bipolar disorder has not yet been well established. However, the reader is advised to review these approaches in addition to the other techniques described below.
The standard strategy for treating bipolar disorder is to prescribe two medications: An antidepressant (to treat the depression) and a mood stabilizer (to prevent manic episodes and cycling). More recently, some of the atypical antipsychotic medications have also been used in place of, or in addition to, mood stabilizers (see Chapter 4 for details). The antipsychotics are particularly useful in cases where psychosis is present. (The medication Symbyax, which is a combination of the antidepressant Fluoxetine and the atypical antipsychotic Olanzapine, has been approved for use in treating the depressive phase of bipolar disorder. Information about Symbyax may be found in Section 2.5.3.)
Antidepressants are described in Chapter 2, while mood stabilizers are described in detail in the following sections. While no widely-accepted test exists to identify the most appropriate medications for a particular person, the experimental technique of Section may be worth investigating for this purpose.
The mechanisms by which mood stabilizers work are even less well-understood than those of antidepressant medications. While the latter are thought to exert their effects most often by increasing the concentration of neurotransmitters (specifically serotonin, norepinephrine, and dopamine), the mechanisms of mood stabilizers are less understood and more varied in nature.
Some of the mood stabilizers prescribed for bipolar disorder are occasionally prescribed for unipolar depression, either solely, or in combination with other antidepressants. While this type of augmentation is not uncommon, its effectiveness is not well understood.

Warning! It is very important that anyone suffering from bipolar disorder not take any antidepressant that increases serotonin concentration (such as the SSRI, SNRI, TCA, and MAOI categories), without taking a mood-stabilizer medication at the same time. Taking one of these antidepressants without a mood stabilizer can trigger manic states. If you find that taking one of these antidepressants leads to excessive spending, grandiose behavior, hyperactivity and insomnia, consult your psychiatrist immediately. You may have bipolar disorder, and require an appropriate treatment for it.

3.4  Lithium

Lithium compounds have been used for a very long time, relative to other psychotropic medications. Lithium's beneficial effects on stabilizing the moods of people suffering from bipolar disorder (long before the illness had that name) were noticed in the late 1800s, although the Food and Drug Administration (FDA) did not approve lithium for this medical use until 1970.
Lithium was the the only FDA-approved medication for chronic mania until 2004, when Olanzapine (an anti-psychotic medication) was approved for this use.

3.4.1  Mechanism

The mechanism by which lithium alleviates mania is not known, although some things are known about its effects on neurochemistry. Lithium may exert a dual effect on receptors for the neurotransmitter glutamate, regulating the glutamate concentration so that it stays between minimum and maximum limits (see, for example, the description at bipolar.about.com/cs/lithium/a/0103_lithium1.htm). It also alters sodium transport in nerve and muscle cells and increases the metabolism of catecholamines (epinephrine, norepinephrine, and dopamine) in the brain.

3.4.2  Benefits

Lithium compounds are used to treat the manic episodes of bipolar disorder. They are sometimes prescribed to augment the effect of antidepressants in the treatment of unipolar depression, and to treat Obsessive-Compulsive disorder. They are highly effective (as psychotropic medications go), with approximately 60-80% rate of success for classic mania (30-40% or dyshporic/psychotic mania or mixed states, 20-30% for rapid-cycling bipolar-affective disorder).

3.4.3  Principal Drawbacks

The amount of lithium required for optimum treatment of mania is, unfortunately, not much less than the amount at which toxicity appears. Thus it is important to monitor the concentration of lithium in the blood carefully, to ensure that it does not rise above the threshold for toxic effects. The most common side effects are gastrointestinal (GI) problems (nausea, vomiting, diarrhea), weight gain, and tremor. GI problems and muscular weakness may be early symptoms of lithium toxicity, and should be reported to the physician immediately. Renal (kidney) function should be checked periodically (usually annually) to look for signs of trouble.
Lithium can cause hypothyroidism, a condition in which the thyroid gland produces inadequate levels of thyroid hormones (see Section 1.5. Thus thyroid function should also be checked periodically (typically on an annual basis).

Warning! Lithium has the second-highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level have been associated with QT Prolongation, but not proven to cause it. The risk for QT Prolongation is not considered high, but medications with lower risk are preferred, especially for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.

3.4.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Lithobid Lithium Carbonate Lithium salt 24 hours 5 days Bipolar Disorder (Manic phase) Depression (Adjunctive)
Priadel Lithium Citrate Lithium salt (liquid form) 24 hours 5 days Bipolar Disorder (Manic phase) Depression (Adjunctive)

3.4.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Lithium Carbonate Lithobid, Camcolit, Carbolit, Carbolith, Carbolithium, Ceglution 300, Ceglution, Contemnol, Duralith, Eskalith, Eskalith-Cr, Hynorex Retard, Lentolith, Licab, Licarb, Licarbium, Lidin, Limas, Liskonum, Litarex, Lithane, Litheum 300, Lithicarb, Lithionate, Lithizine, Lithocap, Lithonate, Lithotabs, Litilent, Litocarb, Maniprex, Milithin, Neurolepsin, Neurolithium, Phanate, Phasal,Plenur, Priadel Retard, Priadel, Quilonium-R, Quilonorm Retardtabletten, Quilonum Retard, Quilonum SR, Teralithe, Theralite
Lithium Citrate Priadel

3.5  Valproate

Valproate (used generically for this category) is an anticonvulsant medication that has been found effective for the treatment of the manic episodes of bipolar disorder. Valproate is also prescribed to prevent migraine headaches, in addition to its use in treating seizures and bipolar disorder.

3.5.1  Mechanism

The mechanism by which Valproate alleviates mania is not known. It has been suggested that its activity in the treatment of epilepsy is due to increasing the brain concentration of Gamma-aminobutyric acid (GABA). However, Valproate appears less likely to cause sleepiness than medications known to boost GABA, which may indicate that Valproate's effect on mania works in some other fashion.
Note that Divalproex is a mixture of Sodium Valproate and Valproic Acid.

3.5.2  Benefits

Valproate is effective in treating mania and seizures.

3.5.3  Principal Drawbacks

Valproate can cause liver (hepatic) damage or failure. Thus it is important to conduct blood tests to monitor the liver function in patients who are taking this medication, and terminate the medication if liver damage is detected. Valproate can also cause birth defects, if taken by pregnant women, or pancreatitis (inflammation of the pancreas). Any abdominal pain, nausea, or vomiting that occurs after beginning treatment with Valproate should be reported to a doctor immediately for diagnosis.
Weight gain is also a common, though not universal, side effect.
The different formulations of Valproate (in the table below) work in the same fashion inside the body (once converted into Valproate ions after ingestion), but are not identical in terms of dosage. Exercise care when converting from one formulation to another.

3.5.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Depacon Sodium Valproate  24 hours 5 days Bipolar Disorder (Manic phase); Seizures (Monotherapy, Adjunctive) Depression
Depakene Valproic Acid  24 hours 5 days Bipolar Disorder (Manic phase); Seizures (Monotherapy, Adjunctive) Depression
Depakote Divalproex  24 hours 5 days Bipolar Disorder (Manic phase); Seizures (Monotherapy, Adjunctive) Depression

3.5.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Divalproex Depakote, Convulex, DPA, Depakene, Depakine, Dipropylacetic acid, Divalproex sodium, Elvetium, Epilim, Epival, Ergenyl, Everiden, Mylproin, N-dipropylacetic acid, N-DPA, Novoseven, Propylvaleric acid, Valcote, Valnar
Sodium Valproate Depacon, Convulex Syrup, Convulex, Depakene, Depakin, Depakine Depakote, Druppels, Depakine, Depakote, Depalept Chrono,Depalept, Epilam, Epilex, Epilim Chrono, Epilim, Epival, Ergenyl, Leptilan, Orfil, Orfiril, Orfiril Retard, Petilin, Valcote, Valeptol, Valoin, Valpakine, Valparin, Valporal, Valprax, Valpro, Valsup
Valproic Acid Depakene, 2 PP (base), Alti-Valproic, Bruceine D, Convulex, DPA, DPA (VAN), Delepsine, Depacon, Depakin, Depakine, Deproic, Di-n-propylacetic acid, Di-n-propylessigsaure, Dipropylacetic acid, Dom-Valproic, Epiject, Epilex, Epilim, Epival, Ergenyl, Kyselina 2-propylvalerova, Leptilan, Med Valproic, Mylproin, Myproic Acid, N-Dipropylacetic acid, N-DPA, Novo-Valproic, Nu-Valproic, Orfiril, Penta-Valproic, 2-propyl-Pentanoic acid, Propylvaleric acid, Sodium hydrogen divalproate, Sprinkle, Valcote, 2-propyl-Valeric acid, Valparin, Valporal, Valpro, Valproate semisodique, Valproate semisodium, Valproato semisodico, Valproatum seminatricum, Valprosid

3.6  Enzyme-Inducing Anti-Epileptic Drug (EIAED)

This category is defined not by how the medications achieve their therapeutic results, or by their chemical structure, but by their effects on the liver. EIAED medications induce (cause) the liver to create more of the CYP450 enzyme. A dose that was effective initially may need to be raised over time, as the liver produces more of the enzyme, and breaks down the medication faster.

3.6.1  Mechanism

The mechanism by which these medications alleviate mania and seizures is not known.
Oxcarbazepine is chemically similar to Carbamazepine, but has an extra oxygen atom.

3.6.2  Benefits

These medications are effective in treating mania and seizures.
Oxcarbazepine's tendency to cause drowsiness may be useful for people who have difficulty sleeping.

3.6.3  Principal Drawbacks

Because of their enzyme-inducing effects, the dosage may need to be raised over time in order to maintain a constant level of effectiveness. Also, changing the liver's behavior in this fashion affects other biochemical processes that involve the liver. As a result, there can be numerous drug-drug interactions, including those that involve hormones and birth-control pills. Anyone considering a major change in diet should consult a doctor beforehand, as they can also have unexpected results (such as disruption of glucose processing). In general, one should be sure to discuss possible problems with the doctor, and keep them in mind when taking medications or altering eating habits.
Carbamazepine commonly causes nausea, confusion, fatigue, dulled thinking, and clumsiness (often temporary). Rarely, Carbamazepine can cause aplastic anemia and agranulocytosis. Periodic blood samples should be taken to monitor for these problems. Immediately report to physician any rash, fever, sore throat, or easy bruising.
Oxcarbazepine commonly causes somnolence, tremor, abnormal gait. Oxcarbazepine can also cause an odd, dangerous, but easily treatable condition known as hyponatremia. Nausea, fatigue, seizures, and dulled thinking should be reported to the physician immediately.

3.6.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Tegretol Carbamazepine Tricyclic 16 hours 3 days Seizures (Partial, not Absence) Bipolar Disorder (Manic phase)
Trileptal Oxcarbazepine Tricyclic 11 hours 3 days Seizures (Partial, Monotherapy and Adjunctive) Bipolar Disorder (Manic phase)

3.6.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Carbamazepine Tegretol, Apo-Carbamazepine, Atretol, Biston, Calepsin, Camapine, Carbadac, Carbamazepen, Carbamezepine, Carbatol, Carbatrol, Carbazene, Carbazep, Carbazepine, Carbazina, Carbelan, Carbium, Carmaz, Carpaz, Carzepin, Carzepine, Clostedal, Convuline, Degranol, Epileptol, Epileptol CR, Epitol, Eposal Retard, Equetro, Espa-lepsin, Finlepsin, Foxalepsin, Foxalepsin Retard, Hermolepsin, Karbamazepin, Kodapan, Lexin, Macrepan, Mazetol, Neugeron, Neurotol, Neurotop, Neurotop Retard, Nordotol, Novo-Carbamaz, Nu-Carbamazepine, Panitol, Sirtal, Stazepin, Stazepine, Tardotol, Taro-Carbamazepine, Taro-Carbamazepine Cr, Taver, Tegol, Tegretal, Tegretol, Tegretol Chewtabs, Tegretol Cr, Tegretol-Xr, Telesmin, Telestin, Temporal Slow, Temporol, Teril, Timonil, Timonil Retard
Oxcarbazepine Trileptal, Oxaprozin, Oxaprozine, Oxcarbamazepine

3.7  GABA Analogs (GA)

The medications in this category are those which increase the concentration or effects of GABA, and are not otherwise categorized.

3.7.1  Mechanism

The classification of Gabapentin is uncertain. It is not defined as a GABA agonist, although it is structurally related to GABA, and binds to some sites in the neocortex and hippocampus of the rat brain. Gabapentin is also not a reuptake inhibitor of GABA, serotonin, norepinephrine, or dopamine, nor does it convert into GABA or a GABA agonist. The mechanism by which Gabapentin alleviates seizusres is not known. The mechanism by which it alleviates pain from neuralgia is also not known.
Tiagabine is a selective GABA reuptake inhibitor (GRI). It increases the concentration of GABA in the brain by binding to the GAT-1 transporter, which is the protein predominantly responsible for reuptake of GABA into the presynaptic (emitting) neurons and glial cells.

3.7.2  Benefits

These medications are effective in treating mania and seizures.
Gabapentin is an effective treatment for herpes-induced pain and seizures. Its effectiveness in treating bipolar disorder has not been well established.
Tiagabine is an effective treatment for mania and seizures, though like all psychotropic medications, it is not always effective in all people.

3.7.3  Principal Drawbacks

Typical side effects include dizziness, somnolence, and fatigue. Gabapentin has the odd features of not being metabolized significantly (it is excreted in unaltered form), and its concentration in the body does not increase in proportion to the dose. The higher the dose, the smaller the percentage of the medication is actually absorbed by the body. The result is that the amount in the body does increase with dose, but at decreasing rates.
Tiagabine is reputed to work well for 7-10 days in many people, as a treatment for bipolar, panic, and post-straumatic stress disorders, then suddenly stop. The transient benefit can be quite frustrating. Typical side effects include dizziness, somnolence, irritability, fatigue, nausea, and tremor.

3.7.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Gabitril Tiagabine  8 hours 2 days Seizures (Partial, Adjunctive) Bipolar Disorder (Manic phase); Generalized Anxiety Disorder; Panic Disorder; Post-Traumatic Stress Disorder
Neurontin Gabapentin  6 hours 1 day Seizures (Partial, Adjunctive); Neuralgia (Postherpetic, i.e., from Herpes infections) Bipolar Disorder (Manic phase)

3.7.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Gabapentin Neurontin, Aclonium, Gabapentine, Gabapentino, Gabapentinum, Gabapetin, Novo-Gabapentin
Tiagabine Gabitril, Tiagabina, Tiagabinum

3.8  Miscellaneous Anticonvulsants

The medications in this category are those that have not been otherwise categorized.

3.8.1  Mechanism

The mechanism by which Lamotrigine alleviates bipolar disorder is not known. What is known is that it weakly inhibits serotonin receptors. It does not inhibit the reuptake of norepinephrine, dopamine, or serotonin. It lengthens the intervals between the occurrence of mood episodes (depression, mania, hypomania, and mixed episodes) in patients who are treated for acute mood episodes with standard therapy (such as with Valproate). (Ideally, Lamotrigine would lengthen the interval between episodes to the point where the episodes no longer occur, but this cannot be guaranteed.)
The mechanism by which Topiramate alleviates seizures is not known. What is known is that it increases the effectiveness of GABA, by increasing the frequency at which GABA activates GABA receptors.

3.8.2  Benefits

These medications are effective in treating mania and seizures.
Lamotrigine is an effective treatment for bipolar disorder and seizures. Compared to other mood stabilizers, it is unusual in that it does not act primarily to suppress mania, but rather to reduce the severity and frequency of the extremes of bipolar disorder (manic and depressive states). It has been found to be of benefit in treating normal (unipolar) depression, as well the depressive phase of bipolar disorder.
Topiramate is an effective treatment for seizures, though like all psychotropic medications, it is not always effective in all people.

3.8.3  Principal Drawbacks

Although this problem occurs rarely (roughly 1 out of 1000), Lamotrigine can cause a dangerous rash, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. The rash can cause serious tissue damage, and even death. The risk of developing the rash is greater for pediatric patients than adults, or for people who are taking Valproate (which approximately doubles the elimination half life of Lamotrigine). If such a rash occurs, it is most likely to occur within 2 to 8 weeks after starting the medication (though there is no guarantee that one won't occur later).
The risk of a dangerous rash is reduced if one slowly increases the dosage from a small quantity to the therapeutic level. Thus one typically receives a starter pack of Lamotrigine customized for increasing the dose to useful levels at a controlled rate.
While the rash issue is serious, the possibility should not deter someone who may benefit from the medication from trying it. The physician and patient should simply be careful to monitor for any adverse reactions.
In spite of the caution about rashes, Lamotrigine generally has little in the way of side effects. For people who take Lamotrigine as a seizure treatment, the more common side effects include headache, nausea, dizziness, clumsiness, drowsiness, runny nose, rash, and double or blurred vision. For those who take it as a bipolar treatment, side effects are less common; of these, the more common side include back, neck, or abdominal pain, nausea, constipation, insomnia, drowsiness, runny nose, and rash.
Care must be exercised when combining Lamotrigine with Valproate, due to the effects of the latter on the chemistry of the former. The dosage of Lamotrigine may need to be adjusted downwards relative to what would be considered appropriate in the absence of Valproate.
Rarely, myopia and glaucoma can develop, so the patient should report any new vision problems immediately. Common side effects include fatigue, dizziness, clumsiness, tremor, impaired speech, nausea, weight loss, drowsiness, nervousness, memory impairment, loss of appetite, depression, and decreased attention span.

3.8.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Lamictal Lamotrigine Phenyltriazine 33 hours 7 days Bipolar Disorder (General), type I; Seizures (Partial, Monotherapy or Adjunctive); Seizures (Generalized, Adjunctive) Depression
Topamax Topiramate Monosaccharide 21 hours 4 days Seizures (Adjunctive) Bipolar Disorder (General), type I; Depression

3.8.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Lamotrigine Lamictal, Lamictal Cd, Lamotrigina, Lamotriginum
Topiramate Topamax, Tipiramate, Tipiramato, Topamax (TN), Topamax Sprinkle, Topiramato, Topiramatum

3.9  Benzodiazepines

Medications in the Benzodiazepine category are typically prescribed for Anxiety and Panic Disorders, and as an aid in sleeping. Some of them are also of use in treating seizure and bipolar disorders.

3.9.1  Mechanism

Benzodiazepines enhance the activity of Gamma-aminobutyric acid (GABA), which has a calming effect on the brain. They are anticonvulsant medications, useful in treating seizures, and like other anticonvulsant medications, are often useful in treating bipolar disorder as well.

3.9.2  Benefits

Benzodiazepines are relatively weak mood stabilizers. Their principal advantage is that they work quickly, and can be a good choice when a seizure or manic episode is starting. They may are useful in the long-term treatment of anxiety in the event that more standard antidepressants are unsuccessful.
Lorazepam is particularly fast-acting, with minimal side effects.

3.9.3  Principal Drawbacks

Because they are relatively weak mood stabilizers, Benzodiazepines are generally not a good choice for long-term control of mania. Also, they are addictive, and can aggravate depression (unipolar or bipolar).
Alprazolam is considered to be one of the most, perhaps the most, potent and addictive of all benzodiazepines.

3.9.4  Medications

Main Brand Name Chemical Name Chemical Type Half Life Washout Time On-Label Uses Off-Label Uses
Ativan Lorazepam Benzodiazepine 18 hours 4 days anxiety; Seizures Bipolar Disorder (Manic phase); Insomnia
Klonopin Clonazepam Benzodiazepine 36 hours 1 week Panic Disorder (with or without agoraphobia); Seizures (Monotherapy, Adjunctive) Bipolar Disorder (Manic phase)
Librium Chlordiazepoxide Benzodiazepine 36 hours 1 week anxiety Bipolar Disorder (Manic phase)
Tranxene Clorazepate Benzodiazepine 2 days 10 days anxiety; Seizures (Adjunctive) Bipolar Disorder (Manic phase)
Valium Diazepam Benzodiazepine 2 days 10 days anxiety; Muscle Spasms Bipolar Disorder (Manic phase)
Xanax Alprazolam Benzodiazepine 11 hours 4 days Panic Disorder (with or without agoraphobia) Bipolar Disorder (Manic phase)

3.9.5  Brand Names

Chemical Name Brand Names (Principal in Bold)
Alprazolam Xanax, Alplax, Alpronax, Alviz, Bestrol, Cassadan, Constan, D 65MT, Esparon, Frontal, Intensol, Niravam, Restyl, Solanax, TUS-1, Tafil, Tranax, Trankimazin, Tranquinal, Xanax XR, Xanor
Chlordiazepoxide Librium, A-Poxide, Abboxide, Apo-Chlordiazepoxide, Balance, CD 2, CDO, CDP, Chloradiazepoxide, Chlordiazachel, Chlordiazepoxid, Chlordiazepoxide Base, Chlordiazepoxidum, Chloridazepoxide, Chloridiazepide, Chloridiazepoxide, Chlorodiazepoxide, Chlozepid, Clopoxide, Clordiazepossido, Contol, Control, Decacil, Eden, Elenium, Helogaphen, Ifibrium, Kalmocaps, Librax, Librelease, Librinin, Libritabs, Limbitrol, Limbitrol Ds, Lygen, Menrium, Mesural, Methaminodiazepoxide, Mildmen, Multum, Napoton, Napton, Novo-Poxide, Psicosan, Radepur, Risolid, Silibrin, Tropium, Viopsicol
Clonazepam Klonopin, Antelepsin, Antilepsin, Chlonazepam, Cloazepam, Clonazepamum, Clonopin, Iktorivil, Klonopin, Klonopin Rapidly Disintegrating, Landsen, Rivotril
Clorazepate Tranxene, Chlorazepate, Chlorazepic acid, Clorazepate dipotassium, Clorazepic acid, Clorazepic acid, Gen-xene
Diazepam Valium, Alboral, Aliseum, Alupram, Amiprol, An-Ding, Ansiolin, Ansiolisina, Apaurin, Apo-Diazepam, Apozepam, Armonil, Assival, Atensine, Atilen, Bensedin, Bialzepam, Calmocitene, Calmpose, Cercine, Ceregulart, Condition, DAP, Diacepan, Dialag, Dialar, Diapam, Diastat, Diazemuls, Diazemulus, Diazepam Intensol, Diazepan, Diazetard, Dienpax, Dipam, Dipezona, Dizac, Domalium, Duksen, Duxen, E-Pam, Eridan, Eurosan, Evacalm, Faustan, Faustan, Freudal, Frustan, Gewacalm, Gihitan, Horizon, Kabivitrum, Kiatrium, LA III, La-Iii, Lamra, Lembrol, Levium, Liberetas, Mandrozep, Methyldiazepinone, Methyldiazepinone, Pharmaceutical, Morosan, Neurolytril, Noan, Novazam, Novo-Dipam, Paceum, Pacitran, Paranten, Paxate, Paxel, Plidan, Pms-Diazepam, Pro-Pam, Q-Pam, Q-Pam Relanium, Quetinil, Quiatril, Quievita, Relaminal, Relanium, Relax, Renborin, Ruhsitus, S.A. R.L., Saromet, Sedapam, Sedipam, Seduksen, Seduxen, Serenack, Serenamin, Serenzin, Servizepam, Setonil, Sibazon, Sibazone, Solis, Sonacon, Stesolid, Stesolin, Tensopam, Tranimul, Tranqdyn, Tranquase, Tranquirit, Tranquo-Puren, Tranquo-Tablinen, Umbrium, Unisedil, Usempax Ap, Valaxona, Valeo, Valiquid, Valitran, Valrelease, Vatran, Velium, Vival, Vivol, Zetran, Zipan
Lorazepam Ativan, (+/-)-Lorazepam, Almazine, Alzapam, Anxiedin, Aplacassee, Bonatranquan, Delormetazepam, Emotival, Idalprem, L-Lorazepam Acetate, Lorabenz, Lorax, Loraz, Lorazepam Intensol, Lorsilan, O-Chlorooxazepam, O-Chloroxazepam, Pro Dorm, Psicopax, Punktyl, Quait, Securit, Sedatival, Sedazin, Somagerol, Tavor, Temesta, Wypax

3.10  Antipsychotics

The newest category of medications used for the treatment of bipolar disorder is that of the atypical antipsychotics. These medications were originally developed to treat schizophrenia, as well as psychosis arising from various conditions, including bipolar disorder.
The antipsychotic medications that have been found to be useful for treating bipolar disorder are described in Section 4.5. While it is generally a good thing that additional medications have become available to treat bipolar disorder, the antipsychotic medications are generally less safe, and have more drastic side effects, than mood stabilizers and antidepressants. For this reason, they should be used with caution, and primarily in cases where the illness does not respond to other treatments.
The medication Symbyax, which is a combination of the antidepressant Fluoxetine and the atypical antipsychotic Olanzapine, has been approved for use in treating the depressive phase of bipolar disorder. Information about Symbyax may be found in Section 2.5.3.
For more details about antipsychotic medications, their mechanisms, benefits, and drawbacks, see Chapter 4.