Mood Stabilizers by Anthony Kane, MD Introduction Mood stabilizers are the treatment of choice for bipolar disorder, a condition that often accompanies ADHD. However, these drugs have other clinical uses.
Currently, mood stabilizers are being used to treat patients who display symptoms of violent aggression, impulsivity or agitation. These symptoms are quite common in ADHD, especially in those children who suffer from a number of other co-morbid disorders.
Aggression and Impulsivity Most people have violent thoughts out of frustration, but they will not act on these impulses unless they lose control. People with trouble controlling impulsive behavior frequently act out in an aggressive manner. Aggressive behavior is common in variety of conditions such as:
- ADHD
- Conduct disorder
- Psychotic disorders
- Mood disorders
- Intermittent explosive disorder
- Adjustment disorder
- Personality disorders (mainly paranoid, antisocial, borderline)
- Mental retardation
- Delirium
- Dementia
Many of these disorders are co-morbid with ADHD and ODD. Mood stabilizers can be used to treat these conditions.
Agitation Agitation is a form of severe anxiety associated with motor restlessness. It may lead to inappropriate verbal, vocal, or motor activity. It is associated with strong emotion, anxiety, tension, urgency, and fear, and it may lead to aimless wandering, pacing, cursing, or arguing.
Agitation may accompany:
- Psychosis
- Mood disorders
- Anxiety disorder
- Insomnia
- Dementia
Excessive agitation may occur in a number of disorders that are co-morbid with ADHD and ODD. Mood stabilizers can be used to treat these conditions.
Classification of Mood Stabilizers There is no agreed-upon definition of the term mood stabilizer. We all use the term, but it is nowhere officially defined.
There are about 4 major classes of drugs that are being used as mood stabilizers.
These are:
- Lithium
- Anti-epileptics
- Antidepressants
- Neuroleptics (Anti-psychotics)
We shall now discuss some of these drugs in depth.
Lithium Lithium has been used for the treatment of acute bipolar mania for over 50 years. It is an alkali metal similar to sodium and comes as one of two salt preparations, lithium carbonate or lithium citrate.
In the US, lithium is considered the drug of choice for adults and children with bipolar disorder. However, European psychiatrists do not use lithium in children, and in Israel the largest child psychiatric hospital does not even have lithium on the hospital formulary.
Lithium has multiple complex neurochemical effects, with impact on ion channels, serotonin, dopamine, and norepinephrine neurotransmitter systems, as well as on second messenger systems.
So how does it work? Nobody really knows.
Side effects: Up to 75% of patients treated with lithium experience some side effects. Most of these are minor and can be reduced or eliminated by lowering the lithium dose or changing the dosage schedule.
Endocrine: Lithium has been associated with thyroid abnormalities. Hypothyroidism occurs in up to 35% of patients treated with lithium.
Renal: Lithium inhibits reabsorption of water leading to excessive urination and thirst. There have been some reports of structural kidney damage with long-term lithium use.
Cardiovascular: Lithium disrupts the cardiac conduction system and can cause arrhythmias. These changes are usually not significant.
Dermatological: Lithium can induce or exacerbate acne, which is a problem for adolescent patients. It is also associated with hair loss.
Neurological: Lithium may produce a variety of neurological effects, including muscle weakness, tremor, lethargy, cognitive blunting, and headaches. In children, lithium has been reported to alter EEG patterns and to decrease performance on cognitive testing.
Toxicity Even though lithium has a very long list of side effects, that is not what concerns most physicians. The real concern is the toxicity. The blood levels in which, lithium becomes toxic are not much higher than the levels that are necessary for treatment. This combined with the fact that patients who require ithium treatment usually are not particularly reliable or compliant, makes treatment with lithium somewhat precarious.
Toxic effects of lithium include marked tremor, nausea and diarrhea, blurred vision, vertigo, confusion, and increased deep tendon reflexes. With higher levels, patients may experience more severe neurological complications and eventually experience seizures, coma, cardiac arrhythmia, permanent neurological damage, and death.
Hemodialysis is the only reliable treatment for lithium overdose.
Conclusion You are probably wondering by now after reading this list, why would anyone want to go near this stuff. The bottom line is this. Lithium works, and it probably works better than anything else that we have. This is very important. These conditions, bipolar disorder, aggressive personality disorders, conduct disorder, psychotic disorders, etc., are serious psychiatric conditions. Left untreated, they have serious life long and sometimes life terminating consequences.
Anticonvulsants Valproic acid (Depakene, Valprotate) Valproic acid is a simple bracket chain carboxylic acid currently available in two preparations valproic acid, and divalproex sodium a combination of valproic acid and valproate. Some physicians feel that overall this drug is just as effective as lithium and has less serious side effects. Valproate may have a quicker onset of action than lithium.
Side effects:
- Weight gain
- Tremor
- Dizziness
- Sedation
- Headache
- Nausea
- Indigestion
- Bruising
- Hair loss
Rarely, valproic acid has been associated with fatal hepatic toxicity, hemorrhagic pancreatitis, and agranulocytosis.
Valproic acid may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20.
Carbamazepine (Tegretol) Carbamazepine is an anticonvulsant drug, chemically related to the tricyclic antidepressants.
Carbamazepine is effective in controlling impulsive and aggressive behavior. As a mood stabilizer, it is generally felt to be inferior to both lithium and valproic acid and it has a much worse side effect profile than valproic acid.
Up to 50% of patients receiving carbamazepine experience side effects, and the drug is associated with potentially serious adverse reactions.
Side effects
- Aplastic anemia
- Hepatic toxicity
- Impaired learning and memory
- Emotional affects such as irritability and agitation
- Insomnia
- Changes in vision
- Fatigue
- Nausea
- Water retention
- Weight gain
- Dermatitis
- Pancreatitis
The most commonly seen side effects with this agent in children are drowsiness, loss of coordination, and vertigo. Overdose of Carbamazepine can be fatal.
Oxcarbazepine (Trileptal) Oxcarbazepine is a chemical analogue of carbamazepine. The chemical difference translates to a more favorable adverse-effect profile when compared with carbamazepine.
Side effects
- Dizziness
- Nausea
- Headache
- Diarrhea
- Vomiting
- Upper respiratory tract infection
- Constipation
- Dyspepsia
- Ataxia
- Nervousness
Each of these side effects occurred in at least 5% of patients. Another significant side effect occurring in 2.5% of patients is low sodium blood levels.
Even though oxcarbazepine seems to be a better alternative to carbamazepine, its usefulness in the treatment of agitation, aggression and impulsivity has not been scientifically verified.
Lamotrigine (Lamictal) Although the FDA has approved lamotrigine for use in "mood episodes," studies show that it is only effective in preventing depression. In mania, it seems less effective than other drugs.
Serious rash is it’s only major side effect, and it occurs more frequently in children than in adults. There are no data on lamotrigine’s efficacy as mood stabilizers in children or adolescents.
Gabapentin (Neurontin) The major advantage of gabapentin is its relative safety and lack of interactions with other drugs. Its major drawback is that it doesn’t work. Parke-Davis sponsored a study in preparation to an FDA application for use as a mood stabilizer and found it was no better than placebo. In combination with other medications, gabapentin seems to be helpful in managing anxiety and aggression.
Topiramate (Topamax) Topiramate is yet another anticonvulsant with mood stabilizing effects for some patients. It seems to help with anxiety and a number of eating disorders. It is being used clinically to counteract the weight gain caused by valproic acid.
The most common adverse events were sweating, blurred vision, difficulty sleeping, tremors, and paresthesia.
Levetiracetam (Keppra) Levetiracetam is an anticonvulsant approved in the US in late 1999. There are now anecdotal reports of its action as a mood stabilizer.
Antidepressants There are seven distinct classes of antidepressants. The tricyclic antidepressants and monoamine oxidase inhibitors have been around the longest. The serotonin selective reuptake inhibitors are the most popular antidepressants used today. Three other classes also affect the serotonin system, but have additional affects on other systems. These are the dual serotonin and norepinephrine reuptake inhibitors, the serotonin-2 antagonism/reuptake inhibitors, and alpha2 antagonism plus serotonin-2 and -3 antagonizers. The final category is the norepinephrine reuptake inhibitors.
Antidepressants tend to work slowly. It usually takes several weeks before they begin to work and it may take as much as three months before their full benefit is realized. Most antidepressants cause a weight gain of about ten pounds within the first six months. Many cause sexual dysfunction. They also tend to interact negatively with many other drugs. These drugs must be used carefully in bipolar depression, because they have a tendency to push the patient into a manic episode.
Monoamine Oxidase (MAO) Inhibiters The MAO inhibitors were discovered in the 1950’s and were the first antidepressant drugs. These drugs cause dangerous hypertension reactions in patients who take these drugs and who ate certain common foods (cheese) or used certain medications.
These drugs are still used in patients who fail on safer drugs. They are helpful in controlling depression and anxiety.
Common drugs:
- Phenelzine (Nardil)
- Isocarboxazid (Marplan )
- Tranylcypromine (Parnate )
Tricyclic Antidepressants (TCAs) As mood stabilizers, the newer antidepressants have eclipsed the tricyclic antidepressants. However, in the treatment of ADHD, these drugs are very effective. They help 70% of children who fail on stimulants.
The most common drugs in this category are imipramine (Tofranil), nortriptyline, and desipramine (Norpramin). In practice, we have more clinical experience with imipramine, but there is mounting evidence that desipramine may be the better choice.
Imipramine and desipramine have played an important role in research. These drugs have been used as the control drugs when testing the newer antidepressants. In general, all the newer drugs have been better mood stabilizers than the tricyclic antidepressants. However, the TCAs are still considered a better choice in ADHD children, and in ADHD children with other psychiatric disorders such as depression or anxiety disorder they may work better than the stimulants.
Serotonin Selective Reuptake Inhibitors (SSRIs) These are the most popular antidepressants used today. In general, they work better than the older tricyclic antidepressants and have fewer side effects.
Long-term use of these drugs is associated with significant weight gain and sexual dysfunction.
Common drugs:
- Fluoxetine (Prozac)
- Paroxetine (Paxil)
- Citalopram (Celexa, Cipramil)
- Sertraline (Zoloft)
Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs) Venlafaxine is the paradigm drug in this category. It tends to work better than the SSRIs, but is associated with the increase of aggressive behavior when used together with clonidine.
Other Classes of Serotonin Uptake Inhibiters Nefazodone (Serzone) Nefazodone inhibits serotonin and norepinephrine reuptake. It has an advantage over the SSRI’s in that it causes fewer gastrointestinal side effects and does not cause weight gain or sexual dysfunction.
Mirtazapine (Remeron) Mirtazapine has a weaker antidepressant effect than other drugs, but it seems to be more effective against anxiety disorders. Mirtazapine is associated with significant weight gain early in therapy.
Norepinephrine Reuptake Inhibitors Bupropion ( Amfebutamone, Wellbutrin, Zyban ) Bupropion is a selective norepinephrine and dopamine reuptake inhibitor. It is as effective an antidepressant as the SSRI’s and has fewer side effects. Bupropion does not cause sexual dysfunction and is less likely than other antidepressants to induce mania in bipolar patients.
Reboxetine (Edronax) Reboxetine is a selective norepinephrine reuptake inhibitor similar to Strattera. Reboxetine itself typically doesn't have the disruptive effects on cognitive function or psychomotor performance common to older antidepressants. I have seen this drug used successfully in the management of ADHD patients who did not do well with stimulants or other antidepressants. I have also seen this drug induce Raynaud’s syndrome in one child, which is not a reported side effect of the drug.
This drug is licensed in over 50 countries. However, the FDA declined Pharmacia's license application for the North American market. This was a surprising event, considering the FDA approved a similar drug, Strattera, a short time later. The FDA has not revealed the grounds for the decision, but I have my $uspicion$.
Anti-Psychotic Drugs (Neuroleptics) These are not really mood stabilizers, but in practice they are used short term and in low doses to control some of the symptoms that accompany mood disorders. These drugs have significant long-term side effects and risks so they are not commonly used as a maintenance drug in mood disorders.
Risperidone (Risperdal) There are a lot of ADHD children with bipolar disorder on this drug. It has received FDA approval for the short-term treatment of manic episodes.
The most common side effects are restlessness, tremors, muscle stiffness, sleepiness, nausea, abnormal vision, increased saliva, abdominal pain, and urinary incontinence.
Olanzapine (Zyprexa) Olanzapine is an anti-psychotic drug that has received FDA approval for the treatment of acute mania, although it has on occasion induced mania. On the whole olanzapine is a very effect mood stabilizer and it appears that it might be a good maintenance drug.
Olanzapine has side effects similar to other anti-psychotic drugs, though like other newer anti-psychotics, these side effects are less severe than with older drugs.
Clozapine (Clozaril) Clozapine is effective both in unresponsive mood disorders.
Conclusion There are numerous drugs being used as mood stabilizers and there are going to be a lot more. The current trend is toward using these drugs more often to manage short-term and long-term behavior and mood disorders.
Although these drugs all have serious long-term side effects, they are usually fairly safe short-term if the patient is managed closely.
Anthony Kane, MD ADD ADHD Advances Anthony Kane, MD is a physician and international lecturer.
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