Bipolar Disorder, Treatment with Medication

Introduction. Is it necessary to treat bipolar disorder with medication?

Some people believe that bipolar disorder can be healed with psychotherapy. The question that arises though is how a person can benefit from psychotherapy (counselling/talk therapy) if they are in a state of confusion, are irrational and possibly aggressive. During a manic episode, patients are often in denial about their condition and have no ability to gain insight. The only way to treat patients during acute mania is to use medication. In most of such cases, the psychiatrist must initially hospitalize the patient. After the patient is discharged from the hospital, the psychiatrist can continue the treatment in an out-patient setting. The treatment providers should not add psychotherapy until the patient gains his psychological stability. At that point, the combination of medication and psychotherapy is the best treatment for individuals with bipolar disorder.

The medication treatment of bipolar disorder is one of the biggest challenges in the field of psychiatry. The patient with a bipolar disorder can be compared with someone balancing on a tight rope between mania and depression. Adding too much weight on one side can lead to a collapse. Effective treatment of bipolar disorder requires profound knowledge, experience, and dedication from the psychiatrist and psychologist involved in the process. A big percentage of patients suffering from bipolar disorder need lifelong treatment.

Treatment in different phases of bipolar disorder

As the word “bipolar” suggests, the symptoms of bipolar disorder swing between two opposite emotional and mental states. In one phase the patient experiences the symptoms of emotional “low”, i.e. depression. On the other side of the spectrum, he develops symptoms of an emotional “high”, i.e. mania or hypomania. The common dynamic for the bipolar disorder is that once “unlashed” the illness tends to persist. Only in rare cases an untreated first episode of bipolar disorder comes to a still stand and will not appear again.  

The objective of the treatment in the acute state, regardless mania, or depression, is to suppress the symptoms as fast as possible. The long-term treatment goal is to stabilize the patient between these two extremes, which means keeping his mood and energy on a normal level.

In the acute phase of bipolar disorder, regardless mania or depression, the treatment requires a higher dosage of medication and often a combination of two or three different substances. The goal is to silence quickly the symptoms and to avoid a disaster to patient’s private and professional life.

Classes of medication used in bipolar treatment

The untreated acute phase of bipolar disorder can last for several months. The manic episodes tend to last 3-6 months; the untreated depressive episodes are longer up to one year. The treatment with medication significantly reduces the duration of the episodes. The goal of the treatment between the episodes is to extend stable periods, and in the best-case scenario to keep the patient symptom free lifelong. After two manic phases of bipolar disorder psychiatrists will frame it as a chronic illness, thus the patient needs an ongoing treatment. Untreated bipolar disorder might end in frequently appearing manic episodes, followed by depressive phases. Psychiatrists use the term “rapid cycling” for this type of presentation. Patients who develop rapid cycling are not able to participate in social and professional life. Therefore, fast diagnosing and early beginning of treatment are crucial for the therapeutic success.

Psychiatrists treat bipolar disorder with medication belonging to three main categories: mood stabilizers, antipsychotics, and antidepressants. Treatment of bipolar depression entails a combination of at least two, sometimes three drugs including antidepressants.

Mood stabilizers

The mood stabilizers are psychiatric medications used for treatment of mood swings in bipolar disorder. Mood stabilizers can be used alone or in combination with antipsychotics for treatment of mania and as prophylaxes to prevent manic episodes. Some mood stabilizers are effective only for treatment of mania, the others for bipolar depression. Some of them protect the patients “on both sides”: from mania and from depression.

Lithium

Lithium became the first effective medication in the field of psychiatry and remains until today the “golden standard” for treatment of bipolar disorder. Psychiatrists use the medication lithium in the long-term treatment of bipolar disorder stabilizing mood and preventing the extreme highs and lows. Lithium protects the patients from both, manic and depressive episodes. In most of the patients lithium does not cause any side effects.

Lithium, history

The therapeutic effect of lithium as a mood stabilizer in treatment of bipolar disorder was discovered 1948 by an Australian psychiatrist John Cade. Cade published his findings in Medical Journal of Australia in a paper “Lithium salts in the treatment of psychotic excitement”. Cade was a pioneer and father of psychiatric research. His discovery, similar to Fleming’s discovery of penicillin, in later years changed in the fate of millions of people. The portrait of Cade and the story of his research is presented in the movie “Troubled minds, the lithium revolution”.

Cade himself did not recognize the importance of his discovery. It was the the Danish psychiatrist Mogens Schou who first introduced lithium into psychiatric treatment. He fought for years to lithium accepted for treatment of bipolar disorder. Schou knew the condition very well as his brother suffered from bipolar disorder. Beginning in 1950ties, Schou and his fellow psychiatrist Poul Baastrup conducted experiments on lithium. In 1970 they published, in The Lancet , the result of a double-blind, placebo-controlled clinical trial (evidence based scientific method) proving beyond doubt the healing effect of lithium and establishing lithium as an effective medication for most people with bipolar disorder, including Schou’s brother (P. C. Baastrup et al. Lancet 296, 326–330; 1970).

Treatment with lithium

Lithium is not metabolized in the body and eliminated through the kidneys. The lithium plasma level variates individually. Therefore, the psychiatrist must adjust the lithium dosage in each patient to achieve the full therapeutic effect. Lithium can be used in the phase prophylaxis protecting the patient from mood swings as well as in acute manic phase. In acute mania, lithium intake can also begin immediately. The necessary tests are then carried out in parallel. In the acute phase of mania, a higher plasma level of lithium.

Diagnostic before starting lithium therapy

When starting lithium treatment as a long-term mood stabilizer, initially more frequent monitoring of lithium plasma level is necessary. To keep the plasma level stable, lithium level controls should be performed every three months in younger individuals and every two months in older persons. Additionally, the lithium level should be measured with every dose change or when other medications are added.

Avoiding side effects of lithium

Despite so many years since its beneficiary effect in bipolar disorder has been discovered, lithium remains still the “golden standard”. In most of the patients lithium does not cause any side effects and is not limiting the life quality of the patients. Apart of that Lithium protects patients not only from manic mood swing but also from depressive episodes.

Lithium is eliminated only through the kidneys and not metabolized in the body. The psychiatrist must adjust the lithium dosage individually in each patient not only to achieve the full therapeutic effect but also to avoid side effects. To allow the patient to “sleep through” any potential side effects, a single evening dose of lithium can be used.

One of the side effects of lithium therapy is tremor. Hand tremor is usually observed at the beginning of treatment and is often caused by rapid dose increase or a high serum lithium level. In the majority of the cases tremor can be avoided by gradual increase of the dosage any by keeping the plasma level low, but still therapeutically effective. It would be incorrect to discontinue lithium immediately upon the first occurrence of tremor.

A small percentage of patients treated with lithium might experience interactions with the thyroid gland. People with a predisposition to hypothyroidism or a family history need a closer monitoring during the first year of treatment.

Anticonvulsants with mood stabilizing effect

For decades, lithium salts were the sole option for relapse prevention in bipolar disorder. However, since the early 90s, additional pharmacological therapies, particularly anticonvulsants, have been developed, expanding treatment options.

Valproic acid

It is a mood stabilizer that helps control symptoms during the manic or mixed phases of bipolar disorder. The positive effect of valproic acid on mood swings was already known in the 1960s but then fall into oblivion. Only in the early 1990s, studies were conducted in the United States, and valproic acid has since been used in the treatment of bipolar disorder.

Valproate works by increasing the level of a neurotransmitter called GABA in the brain, which helps to calm the overactive circuits that contribute to bipolar symptoms.

Valproate is mostly used in treatment of acute manic episodes. Some studies also demonstrate its relapse-preventing effect for both manic and depressive episodes. Valproic acid is only approved for the treatment of manic episodes but can be used off label for the treatment of bipolar depression. Recently published research data suggested that Valproate might be more effective than lithium for treatment of mixed states and rapid cycling in bipolar disorder.

Valproic acid is often used in combination with other mood stabilizers or antipsychotics to reduce the risk of relapse. Valproic acid is generally safe and effective. However, regular monitoring with blood tests and clinical assessments excludes potential side effects.

The most common side effects of valproic acid might be weight gain.

Lamotrigine

Similar to other mood stabilizers, except Lithium, Lamotrigine is a newer generation antiepileptic drug. It is used for years as a mood stabilizer in bipolar I and II, especially in the prophylaxis. It received regulatory approval for the treatment and prevention of bipolar depression in over 30 countries. The recent studies have shown that Lamotrigine is exceptionally effective in the treatment of bipolar I depression.

Lamotrigine inhibits sodium channels in the central nervous system, leading to the release of glutamate. It exerts a positive effect on the corticolimbic network function, which is a resultant of abnormal activities of the circuits in bipolar depression. Further research is needed to confirm its efficacy in treating bipolar II disorder and rapid cycling.

Experience suggests that only a higher dose of 200-400 mg/day effectively prevents relapse. It is necessary to start with a low dose of 25 mg and gradually increase it in weekly intervals. Lamotrigine is usually well tolerated by the patient without major side effects. It can be used also during the pregnancy in women with bipolar disorder. In rare cases Lamotrigine can cause an allergic reaction of the skin. Therefore, the dosage of lamotrigine should be slowly increased over few weeks. Because of this limitation Lamotrigine can’t be used immediately in sufficient dosage in treatment of acute mania.

Carbamazepine

The anticonvulsant effect of Carbamazepine is known for 30 years but its use as a mood stabilizer in bipolar disorder began in the mid-nineties. Carbamazepine works by blocking sodium channels in nerve cells. In 1980, it was discovered in Japan that Carbamazepine also has an anti-manic and relapse-preventing effect in bipolar disorder. Carbamazepine is generally well tolerated creating occasional side effects such as allergic skin reactions. Its main problem is the negative pharmacokinetic interactions with other medication which can lead to a sudden drop of their efficacy. The results of double-blind studies comparing the efficacy of carbamazepine with lithium demonstrated a clear superiority of the latter. For these reasons, carbamazepine is being used less frequently and only as a second-line option for relapse prevention in bipolar disorder.

Atypical antipsychotics in treatment of bipolar disorder

Atypical antipsychotics such as risperidone, olanzapine, and quetiapine are well established in the treatment of acute manic phase. They are mostly used in combination with a mood stabilizer. Among them only quetiapine has an approval for relapse prevention and is effective even in bipolar depression.

The side effect profiles of atypical antipsychotics such as drowsiness and weight gain must be taken into account.

Choosing the right mood stabilizer

Choosing the optimal mood stabilizer is crucial for treating bipolar disorder effectively. It’s important to consider the specific symptoms and needs of the individual patient, as well as the potential side effects and interactions with other medications. The goal is to find a medication that provides effective symptom control without causing additional problems or complications.

The following classification of mood stabilizing medication was proposed by Ketter & Calabrese (adapted by Simhandl):

• Type A: lithium, valproic acid, carbamazepine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole

• Type B: lithium, lamotrigine, quetiapine

The above classification is helpful to select the proper medication. The key roles for choosing mood stabilizer are:

• Type A – works against manic, hypomanic, and mixed episodes

• Type B works against depressive and subdepressive episodes

• does not cause a shift to another phase or rapid cycling

• shouldn’t accelerate the progression of the illness.

Treatment in manic phase

During the manic phase the patient’s irrational behaviour can severely affect his social and economic status. The patient can overspend, buying useless but expensive items, gambling or even donating money which can end in a financial catastrophe, or even in a total impoverishment. In the manic state the person’s “moral brakes” are out of control. This can lead to oversexualized or aggressive behaviour causing irreparable damages to him and his family.

Treatment in depressive phase

In the depressive phase the problems are different. The patient suffers of lack on energy, low mood, sleeplessness, and often develops suicidal ideation. Depressive episodes in bipolar disorder are far more common than mania and have more detrimental effect on patient’s live.

In some patients mood stabilizers may be sufficient to modulate the depressed mood. However, the standard treatment for bipolar depression is the combination of an antidepressant and a mood stabilizer. The mood-stabilizing medication improves mood, social interactions and patient’s level of functioning. The sole use of antidepressants in bipolar depression carries the risk of transitioning into a hypomanic or manic phase. The mood stabilizer of choice in treatment of bipolar depression is lithium because of its anti-suicidal properties,

Only one of the atypical antipsychotics, Quetiapine is worth mentioning, as it can achieve good antidepressant effects at doses of 300-600 mg for bipolar depression and is approved for this indication.

Prophylaxis in the treatment of bipolar disorder

For the prophylaxis phase, it is recommended to continue prescribing the substances that have successfully stabilized the patient during the maintenance phase. At this stage of the illness, the patient typically feels much better or is even symptom-free, which often leads to a decrease in motivation to take daily medication. It is important to emphasize to the patient that discontinuing the medication poses a significant risk of relapse.

Treatment roles at a glance

• Motivation: Medication needs to be thoroughly discussed with the patient. Many people with bipolar disorder struggle to accept that they need to take medication long-term or even permanently. Comprehensive conversations can help build acceptance and improve compliance, which leads to treatment success.

• Individualized therapy adjustment: It may take some time to find the right medication. Individual symptoms and side effects need to be considered in the medication treatment plan.

• Regular monitoring: The effect of maintenance and prophylactic phases needs to be regularly monitored.

• Acute mania in bipolar disorder: Mood stabilizers such as lithium, valproic acid, carbamazepine, and lamotrigine, as well as atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, are used. Combinations of both is usually more effective.

• Acute depression in bipolar disorder: Only combinations of mood stabilizers and antidepressants make sense, and antidepressants should not be used alone in bipolar disorder. Quetiapine is an alternative as monotherapy.

Conclusion

Bipolar disorder is a chronic illness characterized by mood swings that range from extreme lows to highs.

Patients with bipolar disorder have a high risk of relapse without medication, making long-term to lifelong medication necessary. However, convincing the patient to comply with medication requires a lot of effort.

To achieve maximum therapy success, an individualized medication approach is required. Bipolar disorder requires a different treatment approach than unipolar depression, so accurate diagnosis is crucial.

Acute mania has received more attention in the treatment of bipolar disorder than depression. However, depressive symptoms often cause greater suffering and last longer. Theay also require effective management. Therefore, clinicians should consider the possibility of bipolar disorder when treating patients with depressive symptoms. Asking about prior manic episodes is a useful diagnostic tool.

The core pillar of the treatment for bipolar disorder is the use of medication. Psychotherapy (counselling/talk therapy) is an important but an auxiliary part of the treatment.

Patients suffering from bipolar disorder often need lifelong monitoring and therapeutic support, including the medication and psychotherapy. An important aspect of the treatment is the creation of a therapeutic alliance between the patient, his family, and the psychiatrist.

When patients meet the above-mentioned requirements, the risk of relapse can be minimized and most of them can live symptom free developing successful social and professional careers.