Psychiatric disturbance may be higher in people with epilepsy than in those with other neurologic or medical illnesses. Depression is the most common psychiatric illness in epilepsy, with a reported prevalence rate of up to 42%.Yet depression is often underdiagnosed and undertreated in people with epilepsy.

Both depression and epilepsy may be caused by common pathogenic variables. Psychological factors are likely critical in determining who has a particular biologic predisposition and will go on to develop depression. Other factors are:

• social stigmatization
• discrimination
• vocational difficulties
• restrictions in activities of daily life

• abnormalities in the synthesis and release of noradrenaline, dopamine, 5-hydroxytryptamine, GABA and corticotrophin-releasing hormone, often due to he combination of a genetic predisposition and psychosocial stressors
• polypharmacy
• anticonvulsant therapy

Anticonvulsants that are implicated in causing depression are phenobarbital, phenytoin, vigabatrin and lamotrigine. In the case of phenytoin, the underlying mechanism may be the lowering of folic acid levels.

The impact of depression on people with epilepsy is significant. In addition to impairing daily functioning, it can lead to greater seizure frequency and less seizure control through sleep deprivation and a failure to comply with medication or due to its role as an emotional stressor. Depressed people may abuse their medication, which can be potentially lethal in high doses and in combination with alcohol and street drugs.

The diagnosis of depression is based on DSM-IV criteria. Feelings of sadness, guilt, self-blame and unworthiness are common. Anergia (lack of activity), anhedonia (unhappiness) and loss of appetite and weight, combined with sleep disturbances are often encountered.

Distinguishing features of epilepsy- associated depression are chronic depression and a relative risk of neurotic traits, such as somatization, selfpity and a history of periods of agitated peri-ictal psychotic behavior. Major depressive episodes are more likely to occur during the interictal phase, while shorter depressive episodes (usually not meeting DSMIV criteria for depression and usually not requiring treatment) often occur peri-ictally. Paranoid or psychotic features may also accompany depression, suggesting psychotic depression.

Other factors are social stigmatization, discrimination, vocational difficulties and restrictions in activities of daily life that contribute to feeling of loss of personal control. Feelings of inadequacy and fear that people will find out about their seizures often results in a lack of confidence to interact socially, withdrawal and isolation. Social difficulties, combined with the strain of living with a chronic disability with unpredictable losses of consciousness, often lead to recurrent feelings of helplessness, embarrassment, loss of dignity and low self-esteem. People with epilepsy often experience feelings of shame and self-blame for their illness.

In addition to psychological factors, underlying brain disturbances, such as the Alzheimer’s group of dementias and cerebral arteriopathies may predispose people with epilepsy to depression. Seizures, poor seizure control, ictal and subictal firing and kindling-like phenomena can also contribute to depression. Some evidence suggests that people with epilepsy of left temporal-lobe origin, especially those with underlying brain damage that produces seizures, are more predisposed to depression, a higher seizure frequency and less seizure control.

Depressed people are less able to take measures to abort or inhibit their seizures by physical or psychological techniques. In a U.S. survey at the Maudsley Hospital, most people reported more seizures when they were tense, depressed, tired or angry. They had fewer seizures when they were happy and calm. In this and other studies, happiness appears to be a powerful anticonvulsant.

The most serious consequence of depression in epilepsy is a high risk of suicide. The suicide rate is reportedly five times higher than that in the general population. For people with temporal-lobe epilepsy, the risk of suicide is 25-fold higher than in the general population.

There is a higher risk of attempted suicide, particularly due to overdoses. Reasons include underlying brain disturbances that cause seizures and depression, the overwhelming feeling of helplessness and hopelessness from uncontrolled and unpredictable seizures, and easy access to the anticonvulsant medications. In people with epilepsy and depression, suicide risk should be continuously assessed.

Differential diagnosis includes manic depression, panic disorder, post-traumatic stress disorder, underlying psychotic disorders, substance abuse, adjustment disorder with depressed mood and complicated grief or bereavement.

Often, an extended period is required for diagnosis, due to the person’s mental confusion and reluctance to disclose information. A thorough mental-status examination should always be performed, assessing mood, affect, and the presence or absence of a thought disorder, hallucinations or delusions, suicidal ideation and risk factors, cognition and anxiety symptoms.

Particular attention should be paid to optimization of seizure control in people with epilepsy and depression. This strategy should be implemented first, before resorting to conventional treatment of depression, which involves both antidepressant medication and psychological therapy.

Optimization of seizure control can alleviate depressive symptoms. Further investigations by EEG, MRI, CT scan, epilepsy monitoring unit, examination of seizure diaries may be necessary. Medication adjustments, consideration of alternative antiepileptic drugs (AEDs) or referral to a neurologist are possible.

Depression and seizure frequency can be alleviated by reducing polypharmacy and, if possible, changing to an AED with psychotropic potential, such as carbamazepine, valproic acid or clobazam, as adjunctive treatment.Folic acid supplements are required, if levels are low.

Behavioral methods, such as relaxation and biofeedback techniques, should be considered.Treatment should always be tailored to an individual and his or her unique situation.

All classes of antidepressants are reportedly successful in treating epilepsy-related depression. Many studies have reported the effectiveness of older tricyclic and heterocyclic agents, monoamine oxidase inhibitors inhibitors (MAOIs) and newer serotonin reuptake inhibitors (SSRIs) in the treatment of depression in epilepsy. Specific agents include but not limited to are amitriptyline, nortriptyline, protriptyline, desipramine, doxepin, trazodone, amoxapine, iproniazid, isocarboxazid, tranylcypromine and fluvoxamine.

When considering antidepressants in epilepsy, several issues must be considered, specifically the efficacy of treatment in this particular setting, effects of medication on the seizure threshold, and antidepressant-antiepileptic drug interactions/side effects.

Antidepressant medications may lower seizure control, which may pose a difficulty in treating depression in epilepsy. Fortunately, they do so in varying degrees. Medications that pose the highest risk of seizures and poor control are the tetracyclic antidepressants (TCAs), e.g., bupropion, maprotiline, mianserin and amoxapine, and tricyclic antidepressants, e.g., tertiary amines: doxepin, trimipramine, clomipramine, imipramine and amitriptyline; secondary amines: desipramine, nortriptyline and protriptyline.

The relationship between antidepressants and the risk of seizures is well documented in a correlational but not in causational manner. The difficulty in verifying a causational relationship lays in challenges with study design, patient population and side-effect reporting.

There is much concern over the use of TCAs. Although studies show that TCAs lower seizure control, their extensive use in people with epilepsy and depression, without much reporting of complications, has led some investigators to conclude that lowering the seizure threshold with modest doses of TCA rarely has clinical significance. Subsequently, a dose-effect relationship of doxepin and its effect on convulsions was weredocumented. At low doses, doxepin was found to increase spike activity, while at high doses, it decreased spike activity. The clinical significance remains unclear.

Other antidepressants shown to improve mood and decrease seizure frequency are trazodone, desipramine and protriptyline. Again, definitive clinical significance is not established. Possible reasons for improvements on these drugs include:

• lower emotional stress, resulting in better seizure control
• a possible direct anticonvulsant effect of antidepressant medication
• the use of low to moderate doses, introduced slowly in the presence of antiseizure medication
• antidepressant selection determined by patient’s behavioral status
• potential drug interaction/hepatic enzyme induction, resulting in potentiation of anticonvulsant level or effect

Many studies, including animal data, overdose studies and clinical data, suggest that older TCAs (especially the tertiary TCAs: amitriptyline and imipramine) and some newer tetracyclic agents (bupropion, maprotiline, mianserin and amoxapine) impose the highest risk of seizures. The highest seizure frequency has been reported with bupropion: between 0.4% and 2.19% in different studies.

The best class of antidepressants to prescribe in peop le with epilepsy and those with abnormal EEGs are the selective serotonin reuptake inhibitors (SSRIs). Animal studies report that fluvoxamine and paroxetine had no effect on seizure threshold and have not found any proconvulsant effects. The incidence of seizures with paroxetine is lower than with fluoxetine, 0.15% versus 0.2% respectively. Older SSRIs have a combined reported frequency of seizures of 0.26%.

Monoamine oxidase inhibitors inhibitors ( MAOIs) may be another good therapeutic choice. Studies indicate that iproniazid, isocarboxazid and tranylcypromine impose a very low risk of seizures.

Stimulants such as methylphenidate and D-amphetamine have shown little or no proconvulsant effect. Trazodone has been occasionally reported to be associated with seizures. Electroconvulsive therapy may be considered in those with refractory depression and epilepsy.

In terms of drug interactions, antidepressants may cause slight increases in AED levels. This effect is usually not clinically significant and in some cases may account for better seizure control. However, AED levels should be monitored. Particular caution should be exercised when a patient is taking several AED medications. The effect of AEDs on antidepressants is usually reversed. Some AEDs lower antidepressant levels by up to 50%. Higher-than-usual antidepressant requirements for these patients, however, have not been necessary. AED levels and potential adverse drug interactions should be routinely monitored.

Antidepressant medications should not be withheld because of fear or concerns about epileptogenesis. Should seizures worsen with antidepressant use, a neurologic examination may be warranted. Patients’ concerns about taking extra medications should also be addressed.

Current guidelines for management of depression in people with epilepsy recommend choosing agents with a low seizure potential, using the lowest effective dose avoiding sudden dose changes, and using concomitant anticonvulsants only as needed. Should seizures worsen with antidepressant use, a neurologic examination may be warranted. Patients’ concerns about taking extra medications should be addressed.

Seizure risk may be higher in the presence of underlying brain damage and structural disease. Conditions that lower seizure threshold (exhaustion, fever, hypoglycemia, electrolyte imbalance, etc.) and hazardous situations (driving, swimming and operating machinery) should be avoided.

Depending on the severity of the depression, the person with epilepsy-related depression can be reassured that, in most cases, antidepressant therapy is temporary. Alternative treatments, such as electroconvulsive, antipsychotic and psychological therapy may be considered in patients who are intolerant or non-compliant with antidepressant therapy.