It is now well recognized that the psychiatric sequelae of neurological disorders in large part can be and should be treated. Studies by Robinson1 and others, for example, show that patients with post-stroke depression who are adequately treated for the mood disorder recover more physical function than patients who are not.
Among the most common psychiatric symptoms experienced by patients with neuropsychiatrie disorders are
* psychotic symptoms (delusions, hallucinations, ideas of reference),
* mood disturbances (depression, mania, mood lability),
* anxiety (panic attacks, chronic increased anxiety),
* decreased impulse control,
* increased aggression and violence.
In this article, I will discuss the psychopharmacological treatment of these symptoms in patients with the following neurological disorders: brain tumors, cerebrovascular disease, dementia, seizure disorder, and traumatic brain injury.
The annual incidence of brain tumors is approximately 30 per 100 000 persons,2 with these lesions accounting for approximately 10% of all neoplasms and 2% of deaths related to neoplasms.3 In adults, 80% of brain tumors are primary and 20% are metastatic. The location of brain tumors in adults is as follows: posterior fossa, 30%; frontal lobe, 22%; temporal lobe, 22%; parietal lobe, 12%; pituitary gland, 10%; and occipital lobe, 4%.4 The value of knowledge of tumor location in prediction of the emergence of psychiatric symptoms is unclear. While results of many older studies show little or no association between tumor location and psychiatric symptomatology, results of more recent studies suggest possible correlations between location and symptoms (Table 1). Other tumor variables that are significant with respect to the emergence of psychiatric symptoms include invasiveness, the rate of growth, and increase in intracerebral pressure.
Cerebral Vascular Disorders
Cerebral vascular disease is a widespread and significant cause of disability and death in the United States. It commonly results in a cerebrovascular accident (CVA) or "stroke" secondary to embolic, thrombotic, or hemorrhagic phenomena. These events often lead to severe impairment in motor, sensory, and cognitive functioning, as well as significant emotional and psychological stress. Approximately 40% of patients will develop a post-stroke depression, and a smaller but still significant number of patients will experience symptoms of mania, anxiety, or bipolar disorder.
Lesions in the left hemisphere are often associated with symptoms of anxiety, restlessness, tearfulness, aggressive behavior, cursing, displacement, refusal, and compensatory boasting (catastrophic reaction). Lesions in the right hemisphere are associated with an indifference reaction characterized by undue cheerfulness, minimization, and "left neglect." Symptoms of major depression are often seen in patients with lesions in the left frontal lobe, while symptoms of less severe depression are found with lesions in the right or left posterior parietal lobes or the occipital lobe. Emotional outbursts of inappropriate laughing and/or crying are often associated with bilateral lesions, but can occur with any lesion. Anxiety disorders often develop with left cortical lesions, usually in the dorsal lateral frontal lobe. Symptoms of mania are associated with right basaltemporal or orbitofrontal lesions, and bipolar disorder is often associated with lesions in the right basal ganglia or the thalamus.5'6
Possible Associations Between Tumor Location and Psychiatric Symptoms
Other factors that may predispose to the development of symptoms of a mood disorder are the extent of pre-CVA subcortical atrophy and a family history of affective disorders.7
Huntington's disease is an autosomal dominant disorder characterized by cognitive and psychiatric symptoms, as well as dyskinesias. The most common psychiatric symptoms are anxiety, apathy, depression, irritability, mania/hypomania, intermittent explosive behavior, and psychosis. In many cases, the onset of psychiatric symptoms precedes the onset of the movement disorder.8 Tragically, suicide is all too common in this disorder.
Parkinson's disease is characterized by bradykinesia, muscle rigidity, postural instability, and tremor, as well as dementia and depression in many cases. Approximately 20% to 90% of patients with Parkinson's disease have affective symptoms, most commonly major depression or dysthymic disorder.9 Psychiatric symptoms can be attributable to medication side effects, which occur in some patients. Patients having progressive supranuclear palsy often present with abnormal eye movements and parkinsonian symptoms. Psychiatric symptoms include depression, psychosis, irritability, inappropriate laughing or crying, rage attacks, and slowed thought processes.
Friedreich's ataxia is a slowly progressive degenerative disorder of the cerebellum. Psychiatric symptoms associated with this disorder include depression, psychosis, irritability, agitation, and hyper-religiosity.
Wilson's disease is characterized by liver abnormalities, leading to an accumulation of copper and subsequent degeneration of the basal ganglia. Patients with Wilson's disease often present with symptoms of depression, mania, psychosis, aggression against self or others, or sociopathy.
Alzheimer's disease is the most common form of degenerative cortical dementia in the elderly. The disorder is progressive, typically begins after age 55, and is equally common in men and women. Life expectancy is approximately 10 years after diagnosis. Patients with Alzheimer's disease often present with multiple psychiatric symptoms such as delusions, hallucinations, emotional blunting or outbursts, mood disturbances, psychomotor disturbances, and changes in sleep, appetite, and sexual activity.
The majority of patients with seizure disorders are free of significant psychiatric symptoms. There is a growing consensus, however, that a higher incidence of psychotic and depressive symptoms occur in populations of epileptic patients in comparison with the general population.10*11 More controversial is the question of whether a particular constellation of personality traits is associated with temporal lobe epilepsy.12
Side Effect Profiles of Antipsychotic Drugs
Psychiatric symptoms may occur within any or all of the following time frames:
* preictal period - from several seconds (aura) to several days (prodrome) preceding the seizure,
* ictal period - during the seizure,
* postictal period - minutes to hours following the seizure,
* interictal period - extended time (days, weeks, months) between seizures.
Traumatic Brain Injury
Approximately 2 million people in the United States suffer traumatic brain injury each year, with motor vehicle accidents the cause in about 50%. The balance of these injuries are secondary to falls (21%), violence (12%), and sports or recreation accidents (10%).13 Traumatic brain injuries are commonly the result of penetrating wounds, contusions, hypoxia, subdural and intracerebral hematomas, or diffuse axonal damage.
Patients may present immediately or after a period of weeks or months with symptoms of depression, mania, psychosis, and/or anxiety disorders. Certain personality traits such as suspicion, disorganization, anxiety, and argumentativeness may be more pronounced.
PHARMACOLOGIC TREATMENT OF PSYCHOTIC SYMPTOMS
Patients having brain lesions who present with hallucinations, delusions, or thought disorders frequently have a positive response to treatment with standard antipsychotic medication. However, all antipsychotic drugs (particularly conventional neuroleptics) can cause neurological side effects, while some are more likely than others to lower the seizure threshold. In general, patients with brain lesions are more sensitive to both the side effects and the therapeutic effects of drugs and therefore require a lower dose (i.e., "start low, go slow") than patients without such lesions.
In large part, the choice of an antipsychotic drug depends on the side effect profile, because most available antipsychotics are equally effective in decreasing hallucinations, delusions, and thought disorder (Table 2). Because patients with brain lesions are prone to seizures, the drugs most likely to lower seizure threshold (i.e., clozapine, loxapine, chlorpromazine, and thioridazine) should be avoided.
High-potency antipsychotics, especially haloperidol and molindone, appear to be safer choices with respect to seizures.14 While these high-potency agents are more benign with respect to seizure induction, there is a greater risk of extrapyramidal (EPS) side effects with their use.
The novel antipsychotic agent risperidone appears to cause significantly fewer side effects than conventional neuroleptics and, unlike clozapine, does not lower seizure threshold. Antiparkinsonian drugs such as benztropine and trihexphenidyl, which are used to treat EPS, may contribute to delirium, especially when used with tricyclic antidepressants or lowpotency neuroleptics. Amantadine may be used to treat dystonia and parkinsonian side effects, while benzodiazepines may be used to treat akathisia, thus lowering the risk of delirium.
PHARMACOLOGIC TREATMENT OF MOOD DISORDERS
The number of drugs available to treat depression has increased dramatically over the past few years. Although all currently available agents are approximately equal in clinical efficacy, they do differ significantly with respect to side effects.
The tricyclic antidepressants (TCAs) may be particularly problematic in patients with brain disorders due to their anticholinergic and antihistaminergic side effects. In addition, these drugs are often fatal in overdose and can cause cardiac conduction delays. They may also interact with other medications taken by the neuropsychiatrie patient, leading to increased or decreased blood levels of both drugs. Advantages of the TCAs include extensive experience with their use, established therapeutic blood levels in some cases, and low cost.
Monoamine oxidase inhibitors (MAOIs) are often effective in treating depressive episodes in bipolar patients, as well as symptoms of atypical depression. Because MAOIs are also useful in the treatment of panic and anxiety disorders, they may be useful when panic or anxiety symptoms are combined with depressive symptoms. Because the currently available MAOIs are nonspecific and irreversible, approximately 2 weeks must elapse after discontinuation before the enzyme is regenerated to physiologic levels. Patients taking these drugs must avoid tyramine in their diets, as well as sympathomimetic drugs. Noncompliance may lead to hypertensive crisis. These factors may be especially problematic for neuropsychiatrie patients who, as a result of brain dysfunction, experience decreased memory and/or impulse control.
The selective serotonin inhibitors (SSRIs) are much safer in overdose and, in general, have more benign side effect profiles than the TCAs or the MAOIs. In addition, dose titration is frequently unnecessary. All three available SSRIs (fluoxetine, sertraline, paroxetine) can inhibit hepatic metabolism of other drugs, leading to increased levels, with sertraline the least potent in this respect. Of note, among these three agents, paroxetine has the highest risk of anticholinergic side effects. The SSRIs are also useful in treating symptoms of panic, anxiety, and obsessive-compulsive disorder, especially when these symptoms coexist with depression.
Bupropion and maprotiline in high doses may lower seizure threshold more than other antidepressants. Amoxapine may also lower seizure threshold, can be lethal in overdose, and can cause extrapyramidal side effects. Trazodone is safer than the TCAs in overdose, but is sedating and can cause priapism. Venlafaxine, a combined serotonin and norepinephrine reuptake inhibitor, has been available for only a short time. While it appears to have a side effect and safety profile similar to the SSRIs, it can cause a dose-dependent increase in blood pressure, particularly when exceeding 225 mg/day. Nefazodone, the most recent antidepressant to be released, inhibits reuptake of serotonin and norepinephrine and acts as an antagonist at 5-HT2 and alpha-adrenergic receptors. It is reported to be less stimulating and have a lower incidence of sexual dysfunction than the SSRIs, but may cause more orthostatic hypotension than those agents.
For most neuropsychiatrie patients, the SSRIs, venlafaxine, and nefazodone are probably the most appropriate first-line antidepressants. These drugs are significantly less likely to cause anticholinergic and cardiovascular side effects than are the TCAs, are less sedating than trazodone, are less likely to lower seizure threshold than bupropion, and do not require dietary restrictions as do the MAOIs. Although the SSRIs and venlafaxine may cause temporary side effects of insomnia and/or agitation, these can usually be managed with the addition of a small dose of a sedating antidepressant (e.g., trazodone 50 mg) at bedtime.
Stimulants (methylphenidate and dextroamphetamine) are relatively safe and effective alternative mood elevators when the drugs discussed above are ineffective or intolerable in neuropsychiatrie patients.
Buspirone may also be a useful alternative, with reported antidepressant and antianxiety properties in some cases.
Lithium, valproic acid (VPA), and carbamazepine (CBZ) are used most frequently to treat mania and bipolar disorder. They all require routine blood-level monitoring, as well as baseline and periodic assessment of electrolytes, blood urea nitrogen, creatinine, liver function, thyroid function, and complete blood count. They may also be useful in the treatment of aggression and behavioral dyscontrol.
Lithium has some antidepressant as well as antimanic properties and is often used to augment treatment with other antidepressants or mood stabilizers. Neuropsychiatrie patients, however, may be especially vulnerable to side effects of lithium and may be taking other medications that could alter lithium levels (e.g., diuretics). Thus, lithium may be best reserved for cases where there is a personal or family history of positive response to this agent.
VPA and CBZ are both anticonvulsant drugs that also have mood-stabilizing properties. CBZ is a drug of first choice for partial complex seizures (temporal lobe epilepsy) and may also be useful in controlling other types of seizures. It can be especially helpful in neuropsychiatrie patients who have both mood lability and a lowered seizure threshold. Two possible disadvantages of CBZ are its ability to induce hepatic enzymes, leading to multiple drug-drug interactions, and the rare but potentially dangerous hematological side effects of agranulocytosis and aplastic anemia. CBZ can also accelerate its own metabolism and induce hyponatremia, especially in elderly patients.
VPA may also be a practical treatment for patients with mood lability and decreased seizure threshold. It has significantly fewer drug-drug interactions than CBZ, but rarely can lead to hepatic dysfunction. If patients do not respond or are unable to tolerate the side effects of lithium, CBZ, or VPA, then clonazepam, a benzodiazepine with anticonvulsant properties, may be tried, perhaps as an adjunct to these agents.
PHARMACOLOGICAL TREATMENT OF ANXIETY DISORDERS
Drugs commonly used for the treatment of anxiety are listed in Table 3. The benzodiazepines (BDZs) are the most widely used and differ among themselves with respect to speed of onset, half-life, and duration of action. In addition, some but not all are available for intramuscular and/or intravenous administration. As a class, the BDZs are physiologically addicting and patients may experience withdrawal symptoms when they stop these agents abruptly. Neuropsychiatrie patients are often exquisitely sensitive to both the therapeutic effects and the side effects of these drugs. In addition, elderly patients or those with brain dysfunction may have paradoxical responses, such as agitation and disinhibition.15
Alternatives for the treatment of chronic, generalized anxiety include buspirone and the SSRIs.16 Buspirone is nonaddicting and may have some antidepressant properties. It does, however, have a delayed onset of action, as do the SSRIs. Of the SSRIs, paroxetine appears to be the most effective for panic disorder. Although, theoretically, all of the SSRIs should be effective in treating obsessive-compulsive symptoms, only fluoxetine and fluvoxamine have been approved by the Food and Drug Administration for this indication. The SSRIs may be a more efficient treatment for anxiety and depressive symptoms.
Many neuropsychiatrie patients have sleep disturbances severe enough to require pharmacologic treatment. Although the BZDs have been widely used to treat these patients, these drugs can cause paradoxical excitement and next-day sedation and confusion, especially in brain-disordered patients. For acute or short-lived insomnia, Zolpidem, a non-BZD hypnotic, may be a better choice. Chronic insomnia may be best treated by evaluating the patient for an underlying anxiety and/or depressive disorder and treating with an SSRI or buspirone. Although antipsychotic drugs can be quite sedating, they should only be used to treat insomnia in neuropsychiatrie cases when the insomnia is the result of psychotic symptoms.
PHARMACOLOGICAL TREATMENT OF AGGRESSION, VIOLENCE, AND DECREASED IMPULSE CONTROL
Increased aggression, violence, and/or decreased impulse control can be sequelae of many neuropsychiatrie disorders. Although these symptoms are often associated with dysfunction in the frontal and/or temporal lobes, they can occur with any brain lesion. Treatment of these behaviors will depend on the clinical context in which they occur and their duration.17
For the management of acute episodes of violence, aggression, and/or decreased impulse control, the BZDs and antipsychotics are recommended.18 These agents, in general, have a rapid onset of action and may be especially helpful for rapid tranquilization when given together intramuscularly (e.g., haloperidol 5 mg and lorazepam 1 mg). As mentioned above, however, antipsychotics should be avoided, if possible, unless active psychotic symptoms are present.19
The optimal treatment of chronic violent or aggressive behavior or decreased impulse control may be suggested by the nature of the patient's psychiatric or neuropsychiatrie disorder. Patients with brain lesions, which tend to lower seizure threshold, and patients with seizure disorders may be best treated with CBZ or VPA. Patients whose problematic behaviors occur in a setting of mania or bipolar disorder may also benefit from treatment with CBZ or VPA. Lithium may also be useful in this situation, especially if the patient has a personal or family history of positive response to lithium.
If the behavioral dyscontrol symptoms coexist with persistent symptoms of anxiety or depression, buspirone, venlafaxine, nefazodone, or one of the SSRIs would be an appropriate choice.
Propranolol and the other beta blockers may also be useful in the treatment of chronic aggression.20
Because of the increased sensitivity of patients with brain dysfunction to the side effects of conventional neuroleptics, these drugs should be reserved only for the treatment of psychotic symptoms. Also, the combination of lithium and neuroleptics may increase vulnerability to neurotoxicity and confusion. Again, there may be a special role for risperidone in such patients.
Because patients with neuropsychiatrie disorders are likely to have compromised neurological and psychological functioning, the following factors may be especially relevant to their psychopharmacologic treatment:
* increased sensitivity to side effects,
* therapeutic response at lower than usual dose,
* possibility of drug-drug interactions,
* paradoxical reactions to drugs,
* exacerbation or recurrence of previous psychiatric symptoms or syndromes,
* decreased tolerance to alcohol or other recreational drugs, and
* impaired memory and/or impulse control, leading to possible decreased compliance.
The paradox is that while these patients often require medication to manage their psychiatric symptoms, the available agents can often mimic or exacerbate their condition. Thus, nonpharmacological interventions (e.g., environmental manipulation) should always be considered first. If medications are required, a careful evaluation of their adverse effects must occur before they are employed. Further, upon initiation of drug therapy, patients should be monitored closely for a worsening of their symptoms.
1. Robinson RG, Bolduc PL5 Price TR. Two-year longitudinal study of post-stroke mood disorders: diagnosis and outcome at one and two years. Stroke. 1987; 18:837-843.
2. Price TRP, Goetz KL, Lovell MR. Neuropsychiatrie aspects of brain tumors. In: Yudofsky SC, Hales RE, eds. Synopsis of Neuropsychiatry. Washington, DC: APA Press; 1994:361-380.
3. Kurtzke JF. Neuroepidemiology. Ann Neurol. 1984; 16:265-277.
4. Lohr JB, Cadet JL. Neuropsychiatrie aspects of brain tumors. In: The American Psychiatric Press Textbook of Neuropsychiatry. Washington, DC: American Psychiatric Press; 1987:351-364.
5. Eastwood MR, Rifat SL, Nobbs H, et al. Mood disorder following cerebrovascular accident. Br J Psychiatry. 1989; 154:195-200.
6. Sinyor D, Jacques P, Kaloupek DG. Post-stroke depression and lesion location: an attempted replication. Brain. 1986;
7. Starkstein SE, Robinson RG. Neuropsychiatrie aspects of cerebral vascular disorders. In: Yudofsky SC, Hales RE, eds. Synopsis of Neuropsychiatry. Washington, DC: APA Press; 1994:345-359.
8. Folstein SE, Folstein MF, McHugh PR. Psychiatric syndromes in Huntington's disease. Adu Neurol. 1979; 23:281-289.
9. Mayeux R, Stern Y, William JBW, et al. Clinical and biochemical features of depression in Parkinson's disease. Am J Psychiatry. 1986; 143-756-759.
10. Blumer D. Temporal lobe epilepsy and its psychiatric significance. In: Benson FD, Blumer D, eds. Psychiatric Aspects of Neurological Disease. New York: Grune & Stratton; 1975:171-198.
11. McKenna PJ, Kane JM, Parrish K. Psychotic syndromes in epilepsy. Am J Psychiatry. 1985; 142:895-904.
12. Neppe VM, Tucker GJ. Modern perspectives on epilepsy in relation to psychiatry: classification and evaluation. Hosp Community Psychiatry. 1988; 39:263-271.
13. US Department of Health and Human Services. Interagency Head Injury Task Force Report. Washington, DC: US Government Printing Office; 1989.
14. Fenwick P. The nature and management of aggression in epilepsy. J Neuropsychiatry Clin Neurosci. 1989; 1:418-425.
15. Wise MG, Griffies WS. A combined treatment approach to anxiety in the medically ill. J Clin Psychiatry. 1995; 56(suppl 2):14-19.
16. Schweizer E, Richels K. New and emerging clinical uses for buspirone. J Clin Psychiatry. 1994; 12:46-54.
17. Yudofsky SC, Silver JM, Yudofsky B. Organic personality disorder, explosive type. In: Treatments of Psychiatric Disorders: A Task Force Report of the American Psychiatric Association. Washington, DC: American Psychiatric Association; 1989:839-852.
18. Yudofsky SC, Silver JM, Schneider SE. Pharmacologic treatment of aggression. Psychiatric Annals. 1987; 17:397-407.
19. Yudofsky SC, Silver JM, Hales RE. Pharmacologic management of aggression in the elderly. J Clin Psychiatry. 1990; 51(10 suppl):22-28.
20. Silver JM, Hales RE, Yudofsky SC. Neuropsychosis, aspects of traumatic brain injury. In: Yudofsky SC, Hales RE, eds. Synopsis on Neuropsychology. Washington, DC: APA Press; 1994:279-306.
Possible Associations Between Tumor Location and Psychiatric Symptoms
Side Effect Profiles of Antipsychotic Drugs