Bipolar Disorder Medication & Side Effects

To be clear, in Whole Psychiatry, we strive to reduce the use of medication through assessment and treatment of nutrition, hormones, gastrointestinal disorders, immune and inflammatory pathways, detoxification, social rhythm therapy, and educational and supportive psychotherapy. Nevertheless, medications may be needed, although in lower doses and with less polypharmacy.

Medications for Bipolar Disorder fall into three categories

  • Major Tranquilizers (see full table below) –also called anti-psychotics. The common ones that are currently used include Chlorpromazine (Thorazine), Haloperidol (Haldol), Perphenazine (generic only), Fluphenazine (generic only), Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega)
  • Mood Stabilizers-including Lithium and anti-seizure medications See Table below)
  • Minor Tranquilizers-also called long acting benzodiazepines (Klonopin, generic Clonazepam)

The Major Tranquilizers (Antipsychotics)

In general, because of potentially damaging side effects, the medications in this category should be reserved mainly for psychotic conditions. When used consistently, in appropriate doses, and with monitoring of side effects and compliance, the major tranquilizers can significantly enhance the quality of life for many patients with psychotic disorders, including Bipolar Disorder.

There are five main areas of concern with the major tranquilizers: metabolic syndrome, neuroleptic malignant syndrome, tardive dyskinesia, agranulocytosis and in the elderly with psychotic conditions, premature death.

Metabolic Syndrome

There are various definitions of metabolic syndrome, but essentially it a group of symptoms that increase your risk for heart disease, type II diabetes and stroke. It involves weight gain (with its attendant risks of heart disease and musculoskeletal problems), resistance to insulin (moving one toward diabetes), inflammation, and elevated blood lipids (e.g., cholesterol and triglycerides). The majority of psychiatric medications carry this risk, and this argues again, for the Whole Psychiatry approach, in which medication is reduced and lifestyle, nutrients, hormonal supplements, immune regulation are part of the program. The Whole Psychiatry approach sharply reduces the risk of developing the metabolic syndrome, as well as other risks of chronic illness (e.g., dementia, osteoporosis).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a poorly understood, uncommon condition that can be fatal. It appears in patients who have been treated with antipsychotics, and seems to be independent of dosage and length of treatment. These patients present with symptoms of muscle rigidity, elevated temperature, sweating, blood pressure and pulse changes, as well as altered consciousness. It is treatable, but must be recognized quickly for treatment to succeed. The two essential symptoms are the muscle rigidity and elevated temperature. Treatment of NMS requires intensive care unit monitoring of vital signs, kidney function, etc.

Tardive Dyskinesia

Tardive dyskinesia is only one of a variety of muscle movement disorders caused by the antipsychotics. Other disorders include: sudden dystonia, (sudden abnormal muscle movements and spasms), akathisia (an extremely intense form of restlessness that causes people to actually want to “jump out of their skin”–in some patients this agitation can be mistaken for a worsening of the psychotic symptoms, leading to more medication, increased agitation, and even suicide. It is easily and quickly treatable within minutes, once recognized); and Parkinsonism (minimal facial expressiveness, stiff walking movements, and characteristic movements of the hands). All of these movement disorders are treatable and reversible, with the exception of tardive dyskinesia (although there is new evidence that a medication called Aricept-used for dementia, can help, as can certain amino acids in a supplement called Tarvil).

Tardive dyskinesia was thought to occur only after prolonged treatment with antipsychotics, hence the descriptor tardive (late or tardy). ‘Kinesia’ refers to the movement of the muscles, and the prefix ‘dys’ means abnormal. Unfortunately, recent studies and case reports indicate that the onset of this often permanent condition does not seem to be related to time. In fact, tardive dyskinesia has been known, on rare occasions, to occur after the first dose of an antipsychotic medication.

Patients who are most at risk for tardive dyskinesia seem to include the elderly, women, people with depressive disorders, and those with previous brain damage. Frequently, the condition improves and is not permanent if the medication is discontinued, but this may take as long as one or two years. In a significant number of patients it is permanent.

Tardive dyskinesia must be differentiated from the other movement disorders listed above, as the implications for treatment are different. The other disorders are usually easy to treat. It should be emphasized that tardive dyskinesia is not fatal, but is often permanent. Because of the possible permanence of this side effect, the major tranquilizers should only be used in bipolar disorder, schizophrenia, schizoaffective disorders (a combination of depressive and schizophrenic symptoms), Tourette’s syndrome (muscle and vocal tic disorder), and perhaps obsessive-compulsive disorder with tics, which has responded poorly to standard medications. Given the higher risk of tardive dyskinesia in populations with affective disorders, these medications should be avoided in their treatment. A sudden episode of mania can usually be treated and prevented very effectively without these medications. There is some evidence that the newer ‘atypical antipsychotics’ such as Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega) are less likely to cause these effects. Clozaril (see below) is the only anti-psychotic that does not carry with it the risk of tardive dyskinesia. However, Clozaril does carry with it the risk of agranulocytosis.

Agranulocytosis

Agranulocytosis is mainly a concern with Clozaril (occurring in 1.3% of those treated), but may occur with Mellaril, Prolixin, Serentil, Thorazine, and Trilafon as well. It is an uncommon condition that can be caused by many medications used in general medicine. It occurs when the medication causes the body to stop producing a certain type of infection-fighting blood cell. It is potentially life-threatening unless detected early. For this reason, weekly monitoring of blood counts of patients using Clozaril (and less frequently, other medications) is necessary.

One might wonder why anyone would even consider the use of a medication like Clozaril. The answer lies in three facts: Clozaril is the first antipsychotic that does not cause tardive dyskinesia. Clozaril has been statistically shown to be more effective than the standard antipsychotic medications, particularly in treatment-resistant schizophrenia and schizophrenia accompanied by the negative symptom domain. And finally, Clozaril may also reduce the risk of suicide. It is therefore quite a breakthrough for treatment-resistant schizophrenic and treatment resistant bipolar patients. Clozaril was the first of the atypical anti-psychotics–a new group of antipsychotic medications that are possibly more effective due to their selective action at the level of the limbic system (the mediator of emotional response). These new medications [(Risperidone (Risperdal), Olanzapine (Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon). Aripiprazole (Abilify), Paliperidone (Invega)] have little effect on the part of the brain that controls muscle movement (the striatum), and therefore seem to lack the troublesome muscular side effects.

Seroquel (Quetiapine), has recently been shown to have anti-depressant effects in people with bipolar disorder.

How and Where Do the Major Tranquilizers Work?

These medications block the action of the chemical neurotransmitter dopamine, which inhibits nerve cell activity; these drugs seem to target certain areas of the brain that are under dopamine control. This initially results in increased rates of firing in certain areas of the brain; however, after long-term use, when the antipsychotic effect is clinically evident, these nerve pathways are almost completely inactive. It is commonly believed, but not yet proven, that this action is the reason for both the beneficial and adverse side effects of these medications. The specific areas of the brain whose nerve cells communicate via dopamine include:

  • The area that connects the midbrain, limbic system (controlling emotion), and the frontal cortex (controlling executive activity, social awareness, reward and pleasure, and planning), called the mesolimbic, and mesocortical nerve pathways. The action of these medications on this nerve pathway probably accounts for the antipsychotic effects of these medications. These medications also affect the dopamine-containing nigrostriatal pathway, which accounts for the movement disorders associated with these drugs. Medications are currently being developed that may affect only this pathway (Clozaril is such a medication), eliminating many of the side effects caused by the action of these medications on the following areas.
  • The striatum, which controls movement and muscle tone. Drug effects in this area are responsible for the side effects of muscle stiffness, movement disorders, as well as NMS (discussed above) caused by these medications.
    The hypothalamus and pituitary gland, which control hormonal regulation of appetite, milk production, sexual function, and temperature regulation. Medication action in this area is responsible for side effects such as breast enlargement, weight gain, and NMS.
  • The reticular formation, which controls arousal. Medication action in this area accounts for the reduction in emotional reactivity to external stimuli, perhaps improved sensory filtering, as well as sedation.

The Mood Stabilizers

The mood stabilizers include a small group of chemically diverse medications that are useful primarily in the bipolar disorders, although they do have uses in other clinical situations (e.g., borderline personality, dissociative disorders, alcoholism). These medications tend to decrease mood cycling and mania as well as, to a lesser but significant degree, treat depression (lithium). The group includes lithium carbonate (Eskalith, Cibalith, Lithobid), carbamazepine (Tegretol), and valproic acid (Depakote). Klonopin, commonly used in the same disorders as the mood stabilizers, but not a mood stabilizer itself, is an antimanic, antipanic agent that is included in the minor tranquilizer class.

Lithium

Lithium is possibly the most thoroughly studied medication in all of medicine. Literally hundreds of new studies and reports of its effects are published each year. A clearinghouse for information on lithium has been established (The Lithium Information Center; Department of Psychiatry; University of Wisconsin; Madison, Wisconsin). Lithium is used in the treatment and prevention of mania, depression, alcoholism, and possibly cocaine abuse. It is often used to augment the effect of antidepressant medication when there has been a minimal or incomplete response. It has also been reported as useful in cluster headaches (a form of migraine), character disorders with unstable affect, aggressive male prisoners, late luteal phase dysphoric disorder (premenstrual syndrome), OCD (obsessive-compulsive disorders), and, of course, in its original use–in overactive thyroid conditions.

Risks and Side Effects of Lithium

Lithium is a natural element that in many ways is very similar to sodium (a component of table salt). In fact, the kidney, which is very sensitive to measuring the amount of sodium in the body, cannot distinguish between lithium and sodium. This is an important fact to remember since any condition that leads to an excessive loss of body salt (e.g., diarrhea, vomiting, excessive sweating) causes the kidney to react in such a way that it stops the loss of salt through the urine.

If a patient is taking lithium, the kidney inadvertently stops the loss of lithium as well, and this can quickly lead to lithium toxicity-a potentially dangerous situation. Toxic effects of lithium include slurred speech, trouble with coordination and walking, and confusion. These are serious signs requiring immediate attention for a variety of reasons, including the possibility of permanent residual neurological changes, and alterations in heart function.

Lithium use has three primary risks: decreased thyroid function, altered kidney function, and a rare interaction with Haldol (a major tranquilizer). Because of these considerations, the use of lithium must be carefully monitored by periodic monitoring of the amount of lithium in the blood, kidney function, blood counts, thyroid function, and effects on the heart. More common side effects of lithium include upset stomach, diarrhea, tremor, excessive thirst, and increased urination. These side effects can often be avoided by increasing the dose gradually, taking the medication with meals, determining which preparation of lithium works best, and spacing dosage appropriately.

Tremor can be a serious concern for someone who works with his or her hands, but can often be treated by adjusting dosage, or by the use of Inderal. A potentially troublesome effect for women is weight gain, which can be caused through three different mechanisms: a thyroid effect; a hormonal effect (via the hypothalamus, appetite center, and serotonin); and a kidney effect. The cause of the weight gain can be determined by history and symptoms and can be treated appropriately. Nevertheless, this is a valid concern for many women.

The dosage of lithium varies from individual to individual, with most individuals requiring 300-2400 mg per day in divided doses. During a manic episode more lithium is required to obtain the same blood level than when that same patient is not manic. Thus the dosage is not as important as the amount of lithium in the blood. The amount of lithium in the blood must be maintained in a narrow range called the therapeutic range or therapeutic window. If the level of lithium is above the therapeutic window, toxic effects will occur. Side effects are more likely in the higher range of the therapeutic window, and lithium is not effective for manic depression when the level is below the therapeutic window. New research indicates that it is best to keep the dose as low as clinically possible, as long-term kidney effects may be more common than previously thought, and if the medication is used at high levels initially, the doses might have to remain that high for effectiveness.

How and Where Does Lithium Work?

Unfortunately, despite much investigation, we do not know how lithium works. In the body, lithium substitutes for sodium, calcium, potassium, and magnesium. It also interacts with the three main neurotransmitters studied in affective disorders: norepinephrine, dopamine, and serotonin. Finally, it seems to have an effect on the G proteins associated with the receptors on the surface of the nerve cells. On a non-molecular level, lithium seems to normalize REM (rapid eye movement/dream) sleep abnormalities, which are present in the mood disorders. The most common measurement of these REM abnormalities is called REM latency. REM latency is an excellent marker of the likelihood that a depressive disorder will respond preferentially to medication as opposed to psychotherapy. When a person goes into REM sleep too quickly after first falling asleep, they are said to have decreased REM latency. Lithium normalizes REM sleep, as do the antidepressants, moving dream sleep primarily to the second half of the night, where it belongs.

Carbamazepine

It seems clear that there are certain people who will respond best to Lithium (first episode is mania, followed by depression, and full recovery between episodes) and others (mixed states of agitation, paranoia, frequent déjà vu or jamais vu episodes, micropsia, macropsia, extreme self consciousness –-e.g., feeling that people are talking about them, history of head injury, late onset bipolar disorder) respond better to the anti-seizure medications such as Tegretol (carbamazepine) and valproic acid (Depakote). Carbamazepine (Tegretol) is a medication that has been used in the past, primarily for certain seizure disorders. It has also been used for chronic pain syndromes and restless legs syndrome. Chemically it is similar to the tricyclic antidepressants. In the late 1970s researchers at the National Institute of Mental Health (Post, 1990) determined that Tegretol is effective in the treatment of manic-depressive illness (Bipolar Disorder) and possibly depression. This discovery was based on a theory that had been developed in the early 1900s by Kraepelin (1921), who suggested that the spectrum of manic depressive disorders (bipolar type I and II, as well as cyclothymia) shared many similar characteristics with the seizure disorders. Both disorders seem to have a periodic cycle. Initially, the disorder is quiet. This is followed by a pro-drome (warning signs), followed by a severe stage, and finally a return over time to normal. This cycle is repeated and the more often it occurs, the more likely it is to recur spontaneously and without any stimulus. In fact, modern psychopharmacologists often view manic-depressive disorders through this perspective.

Side Effects of Carbamazepine

Carbamazepine causes an increased frequency of abnormalities in the formation of blood cells. These disorders are called aplastic anemia and agranulocytosis, both having to do with a toxic effect of carbamazepine on the formation of different types of blood cells, and both disorders being potentially fatal. These risks require close monitoring of complete blood counts and iron before and during treatment. The occurrence of these disorders is rare, being anywhere from 16-80 cases per million people per year (5-8 times the normal frequency) for individuals who are taking carbamazepine. Patients should be alert for rash, fever, sore throat, or signs of easy bleeding and immediately report these to the physician, as discontinuation of the medication may be necessary.

Toxic effects of excessive doses of carbamazepine include muscular restlessness and twitching, tremor, trouble with balance, coordination, and walking, severe drowsiness, abnormal eye movements, and dizziness. These effects are aggravated by alcohol, and can also be caused when a large number of other drugs (such as erythromycin, an antibiotic; verapamil, a blood pressure medication; cimetidine, for stomach problems; fluoxetine, an antidepressant) are added or increased in dosage. There are many interactions between other medications and carbamazepine. These interactions must always be taken into account to avoid toxicity or a loss of effect of the carbamazepine due to a lowering of the blood level.

Common side effects during the early phases of therapy include dizziness, drowsiness, nausea, vomiting, and changes in thyroid function. Usually these effects are temporary, and certainly they can often be minimized by changing doses and timing of doses.

In order to avoid all of these risks and side effects and to maximize the best response, one must be certain that hormones (thyroid and adrenal), nutrition and diet, and immune function are addressed. The physician must monitor the levels of carbamazepine in the blood, as well as the counts of certain blood cells, iron, and thyroid hormones. The average dosage of carbamazepine is 1000-1200 mg per day in divided doses of 250-500 mg each; however, it is the amount of medication in the blood that is the essential factor. Often, the side effects of carbamazepine lessen, and the dosage must be increased after the beginning of treatment, since the liver becomes adept at breaking down the carbamazepine for elimination from the body. When administered and monitored properly, carbamazepine is a very effective agent in the treatment of the above-mentioned disorders, particularly when the nutritional, hormonal, detoxification, and immune functions are addressed.

How And Where Does Carbamazepine Work?

Despite the analogy between seizures and bipolar disorders, it seems that different properties of the drug may account for its effectiveness in each of the disorders. Chemically, the carbamazepine molecule is very similar in structure to imipramine (Tofranil), one of the early antidepressant, antipanic medications, which is still in use today. But, carbamazepine has diverse effects on certain noradrenaline receptors, GABA receptors (receptors affected by the minor tranquilizers), and a wide variety of other molecules in the nervous system. Because of these diverse effects, it is not at all clear how it works–only that it does work.

Valproic Acid

Valproic acid (Depakote), like carbamazepine, is an antiseizure medication. It is being used more and more frequently in the United States in the treatment of bipolar disorders, (especially in rapidly cycling bipolars and those with mixed features). In fact, it has just become the first new drug approved for first-line treatment of bipolar disorder in 40 years. It is also used to treat schizoaffective disorder, panic disorder, some dissociative disorders, borderline personality disorder, and to assist in withdrawal from the minor tranquilizers, such as valium and xanax, among others.

Risks and Side Effects of Valproic Acid

Valproic acid, a fatty acid, has been in use for seizure disorders in Europe since the 1960s. As a result of this long history, certain risks have been found with the use of this medication. Liver failure, which can result in death, has been reported. For this reason, I always have my patients use a combination of N-acetylcysteine, R-Lipoic Acid and Selenium, as a liver protector (helps metabolize the valproic acid), promoter of glutathione production (a great anti-oxidant and detoxifying agent in the body), neuroprotector, anti-anxiety and perhaps anti-depressant combo.

Nevertheless, liver failure is rare, and having used valproic acid in my practice for over 20 years, I have never seen this occur. At particularly high risk for liver failure, however, are patients on multiple anticonvulsants (e.g., Tegretol or Klonopin [clonazepam]), those with inborn disorders of metabolism, organic brain disease, mental retardation in the presence of a severe seizure disorder, and children (particularly under age 2). As a person advances in age, he or she is significantly less likely to develop this problem.

Valproic acid can also cause decreased platelet counts, which results in abnormal bleeding and bruising. Because of these rare toxic effects, certain tests of liver function and platelets must be monitored both before and during treatment. Patients must report easy bruising, fatigue, muscle weakness, lethargy, swelling of the face, loss of appetite and vomiting to the physician. All of these problems usually occur in the first six months of treatment, if they occur, and thus monitoring should be more intense during that period.

Common side effects of valproic acid include nausea, vomiting, indigestion, diarrhea, tremor, sedation, temporary hair loss, depression, weakness, and abnormal menses.

The blood levels of valproic acid necessary for seizure control (the original use of this drug) may be different than the levels needed for the treatment of the various psychiatric conditions mentioned above. Sufficient research has not been conducted to address this question. Often, it takes several weeks to obtain the best regimen of valproic acid in an individual patient. Certain preparations are slowly released (e.g., sprinkle capsules for children) and better tolerated, but are only available in low strength, requiring that you take numerous pills, at least until your final dose is determined and then larger strength tablets can be used. The dosage range is wide, varying from 125 mg three times per day to as high as 750 mg three to four times per day. As with lithium and carbamazepine, the dose of medication is less important than the actual level of medication in the blood stream.

How and Where Does Valproic Acid Work?

As with lithium and carbamazepine, we do not know the exact mechanism of action of valproic acid in either seizures or bipolar disorders. There is much evidence that it affects the GABA nerve transmission in the brain, which seems to be calming and inhibitory. Increasing GABA activity seems to have antimanic, antipanic, antianxiety, and anti-OCD effects. The GABA system seems to modify the activity level of the noradrenalin system as well, which has a role in bipolar disorders, depression, anxiety, and panic.

Mood Stabilizing medications

Mood Stabilizing medications

Mood Stabilizing and Anticonvulsant Medications Generic Name Age
Depakote divalproex sodium (valproic acid) 2 and older (for seizures)
Eskalith lithium carbonate 12 and older
Lamictal lamotrigine 18 and older
lithium citrate (generic only) lithium citrate 12 and older
Lithobid lithium carbonate 12 and older
Neurontin gabapentin 18 and older
Tegretol carbamazepine any age (for seizures)
Topamax topiramate 18 and older
Trileptal oxcarbazepine 4 and older

Anti-Psychotic Medications used in Bipolar Disorder and Schizophrenia

Brand Name
(Generic name)
Daily dosage Sedative effects Comments
Abilify
(aripiprazole)
2-30mg Low Possibly less weight gain, possible use in bipolar depression (recently refuted)
Clozaril
(clozapine)
300-900 mg High No tardive dyskinesia Risk of possibly fatal blood disorder requires close monitoring
Compazine
(prochlorperazin)
5-10 mg 4X daily High Mainly used for nausea despite same risks of other drugs in this class
Geodon
(ziprasidone)
20mg-80mg Low Stimulating in low doses
Haldol
(haloperidol)
0.5-5 mg Low Also used in Tourette’s syndrome (uncontrollable tics and vocal utterances). No evidence that higher doses are more effective
Loxitane
(loxapine)
5-250 mg Moderate
Mellaril
(thioridazine)
10-800 mg High Some data indicate less likelihood to cause tardive dyskinesia
Moban
(molindone)
5-200 mg Low-Moderate Off the market
Navane
(thiothixene)
5-60 mg Low
Zyprexa
(olanzapine)
2.5-30mg High Severe rapid weight gain, but highly effective
Orap
(pimozide)
1-10 mg Low Used in Tourette’s syndrome
Invega
(palperidone)
1.5-18mg High Active metabolite of risperidone extrapyramidal symptoms, tachycardia and akathesia
Prolixin
(fluphenazine)
1-40 mg Low Can be administered on once-monthly basis
Risperdal
(risperidone)
1-4 mg 2x/day Moderate More effective for negative symptoms; less extrapyramidal symptoms
Saphris
(asenapine)
5-10mg 2x/per day High
Serentil
(mesoridazine)
50-100 mg 3x/day High
Seroquel
(quetiapine)
25-800mg High Mania, anxiety (COMT SNP positive on both allelles), bipolar depression
Stelazine
(trifluoperazine)
1-20 mg 1-2x/day Low
Symbyax
(olanzapine / fluoxetine combination)
6-12mg Olanzapine / 25-50mg fluoxetine High Approved for both phases of bipolar disorder; weight gain
Thorazine
(chlorpromazine)
25-800 mg/day High The first known antipsychotic
Trilafon
(perphenazine)
2-32 mg 1-2x/day Low

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