Psychotropic prescribing in psychiatric disorders in neurological diseases: stroke, traumatic brain injury, multiple sclerosis, and epilepsy

Psychiatric disorders in neurological diseases (PDNDs) are very common, and they bring additional challenges to patient’s management. The current prevalence of psychiatric disorders in patients with neurological disease has been estimated between 24% and 51%. The most common psychiatric problems seen in patients with neurological diseases are mood disorders, particularly depression and anxiety disorders, but a broad spectrum of psychiatric symptoms may be present. These mental health conditions are problematic, because they are associated with poorer physical and social functionality, lower adherence to treatment, greater morbidity, and with higher suicide risk⁽³⁾.

Psychiatric disorders in neurological diseases are at the interface between psychiatry and neurology, and they cross the traditional lines that divide the two specialties. Therefore, the management of PDNDs has special challenges for patients, providers, families, caregivers and institutions, and neither psychiatric nor neurological services alone can adequately address the severity of clinical needs for these patients⁽³⁾.

The delicate neuronal meshwork of the human brain mediates both neurological and psychiatric functions. Diseases that afflict the central nervous system (CNS) are therefore capable to cause both neurological and psychiatric symptoms, and their management requires care so as not to exacerbate symptoms in either domain. In this paper, we discuss the treatment of the common neuropsychiatric manifestation of cognitive dysfunction, depression, anxiety, psychosis, and emotional and behavioral dysregulations, that are common across CNS diseases⁽¹⁾.

Stroke

Stroke patients are at a significant risk for a variety of neuropsychiatric disturbances, the presentation of which is heavily dependent on the location and extent of the stroke itself. These disturbances include dementia, depression, mania, anxiety, psychosis, disinhibition, apathy, and fatigue⁽¹⁾.

Cognitive deficits. The pathophysiology of post-stroke cognitive disorders is similar to that of vascular dementia, with evidence supporting the use of the acetylcholinesterase inhibitors (AchEIs)⁽¹⁾.

Depression. Depression can be one of the most devastating neuropsychiatric symptoms after stroke. It has a prevalence of almost 30% any time after a stroke, and it is associated with increased morbidity and mortality⁽¹⁾. Tricyclic antidepressants (TCAs), selective reuptake serotonin inhibitors (SSRIs) and mirtazapine demonstrated some benefits in clinical trials. A prospective trial demonstrated that statins have a protective effect against the development of post-stroke depression at one year⁽¹⁾.

Mania. Mania is a rare consequence of stroke. A review reported that patients mostly at risk for post-stroke mania are males with right-sided cerebral infarct who have no personal or family history of psychiatric illness. The treatment of post-stroke mania is similar to the treatment of bipolar mania, with evidence supporting the use of valproic acid, carbamazepine and lithium. The use of antipsychotics, especially in the elderly, is recommended only for short term in acute episodes, to reduce the risk of imminent harm to the patient⁽¹⁾.

Anxiety. It is a common comorbid condition after stroke, afflicting 29% of patients, that may respond to antidepressant therapy. Nortriptyline, duloxetine, sertraline and citalopram are effective in the management of post-stroke anxiety. The use of benzodiazepines should be avoided due to cognitive dulling and the risk of delirium, falls, or further ischemic events due to hypotension⁽¹⁾.

Aggression and irritability. These depend on many factors, including pre-stroke psychiatric illness and the extent of cerebral involvement. The prevalence may be 25%. Fluoxetine was found to be effective in treating post-stroke aggression and irritability⁽¹⁾.

Traumatic brain injury (TBI)

The neuropsychiatric symptoms of TBI include impaired cognition, depression, mania, psychosis, mood lability, irritability, posttraumatic stress disorder, and anxiety⁽¹⁾.

Cognitive deficits. These span multiple domains, including arousal, attention, concentration, memory, language, sleep, and executive functioning. Dopamine agonists (including amantadine, levodopa or carbidopa, and bromocriptine), acetylcholinesterase inhibitors, lithium and valproic acid have shown improvements in reducing the cognitive deficits associated with TBI⁽¹⁾.

Depression. SSRIs are considered first-line agents for post-TBI depression. Citalopram and escitalopram have been found to be effective. Serotonin-norepinephrine reuptake inhibitors (SNRI), including venlafaxine and duloxetine, have been found to be effective too. Dopamine agents can be used for augmentation. Caution is advised with the use of bupropion because of its potential to reduce seizure threshold at higher doses⁽¹⁾.

Mania. Mania is a less common but clinically significant result of TBI. Literature regarding the treatment suggests the effectiveness of the mood stabilizers lithium, carbamazepine and valproic acid⁽¹⁾.

Psychosis. In general, the atypical antipsychotics are preferred over typical agents because of their lower rates of extrapyramidal side effects (olanzapine and risperidone). Unusual or treatment-resistant symptoms of psychosis in the setting of a neurological injury may be due to subclinical seizure activity, specifically partial complex seizures⁽¹⁾.

Aggression and irritability. Aggression and irritability are common among patients after TBI and may be transient, may resolve with neurological improvement, or may be persistent. The treatment includes fluoxetine, neuroleptics, beta-blockers, anticonvulsants, lithium, valproate, and carbamazepine. Amantadine administered in the morning and at noon has been shown to decrease the intensity and frequency of post-TBI irritability and aggression⁽¹⁾. Benzodiazepines can be useful in short-term therapy for aggression. The long-term use can perpetuate cognitive dulling, delirium, or a close cycle of dose escalation⁽¹⁾.

Multiple sclerosis

Multiple sclerosis can result in motor, cognitive and psychiatric disturbances, which may occur together or independently. The neuropsychiatric disturbances of multiple sclerosis (that include cognitive deficits, depression, anxiety, mania, psychosis, fatigue and pseudobulbar affect) may occur only during acute exacerbations or as a chronic feature of the disease⁽¹⁾.

Cognitive deficits. Cognitive impairments – including deficits of attention and memory, executive dysfunction and reduced information processing speed – may be present in almost 70% of patients with multiple sclerosis, and they may be present as early as the time of initial diagnosis. Disease-modifying agents such as interferon-beta-1a can prevent or reduce the progression of cognitive deficits⁽¹⁾. Some of the medication can worsen cognition – for example, tizanidine, diazepam or gabapentin. The treatment of sleep difficulties, depression or fatigue can enhance cognitive function⁽²⁾.

Depression. About 30% of patients with multiple sclerosis report depression, and these patients have an increased risk of suicide⁽¹⁾. Suicide rates are 2-7.5 times higher than in the general population. Depression is often associated with fatigue and pain⁽²⁾. Depression occurs no more frequently in people treated with interferon-beta. The standard care for the initiation of interferon beta should include the assessment for depression and, for those with a past history of depressive illness, prophylactic treatment with an antidepressant. The same applies to those disease-modifying biological treatments that are associated with depression (daclizumab, alemtuzumab, natalizumab etc.)⁽²⁾.

SSRIs should be the first-line treatment, given their relatively benign side-effects profile⁽²⁾. Escitalopram, citalopram and sertraline are considered first-line agents because of their lower drug interaction profile. Paroxetine may be effective, too⁽¹⁾. Fluoxetine was effective in a small case series⁽²⁾. Due to the reduced tolerability of side effects in this patients group, medications should be titrated from an initial half dose⁽²⁾. Many patients are prescribed low-dose TCAs for pain/bladder disturbance, therefore SSRIs should be used with caution, and the patients should be observed for serotonin syndrome. For those with comorbid pain, consideration should be given to treating with a selective serotonin and norepinephrine inhibitor (SNRI), such as duloxetine or venlafaxine⁽²⁾. ATCs are in general poorly tolerated. Cognitive behavioral therapy (CBT) is the most appropriate psychological intervention⁽²⁾.

Anxiety. The prevalence of anxiety is up to 50%. Elevated rates are seen for generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social anxiety. Anxiety appears to be linked to perceived lack of support, increased pain, fatigue, sleep disturbance, depression, alcohol misuse, suicidal ideas, and the uncertainty of prognosis in multiple sclerosis⁽²⁾. SSRIs can be used, and in nonresponsive cases, venlafaxine might be an option. Benzodia­zepines may be used for acute and severe anxiety, but only for a maximum four weeks, and they should not be prescribed in the long term. Pregabalin is also licensed for anxiety in this population group, especially where pain relief is required. People with multiple sclerosis respond to CBT⁽²⁾.

Pseudobulbar affect (PBA). Up to 10% of individuals with multiple sclerosis experience pathological laughing or crying (PLC), or another incongruence of affect. It is more common in the advanced stages of the disease, and it is associated with cognitive impairment⁽²⁾. There has been recommended the use of small doses of TCAs (amitriptyline) or SSRI (fluoxetine) in multiple sclerosis. Citalopram, nortriptyline and sertraline have been investigated in people with post-stroke PLC, and they showed reasonable efficacy and rapid response. Valproic acid may be effective. The combination of dextromethorphan and low-dose quinidine is effective. Dextromethorphan plus fluoxetine may have similar effects⁽²⁾.

Bipolar disorder. Mania is twice as common in patients with multiple sclerosis as in the general population⁽¹⁾. For the management of mania, mood stabilizers (lithium and valproic acid), with adjunctive addition of antipsychotics (risperidone or olanzapine in low doses⁽²⁾) and benzodiazepines for severe mania or the occurrence of psychotic features, have been found to be effective. Corticosteroids are a common necessary treatment for multiple sclerosis flares, and it can be a precipitant of mania⁽¹⁾. Lithium can cause diuresis and, thus, it leads to increased difficulties of tolerance in people with bladder disorder. Patients who require psychiatric treatment for steroid-induced mania with psychosis respond well to olanzapine and risperidone⁽²⁾.

Psychosis. Psychosis occurs in 1.1% of this population, and it is relatively uncommon. In a very few cases, psychosis is the presenting complaint of multiple sclerosis. Risperidone or clozapine have been recommended because of their low risk of extrapyramidal side effects. On this basis, olanzapine, aripiprazole and quetiapine might also be possible options. Psychosis may rarely be the presentation of a multiple sclerosis relapse in which case steroids may be beneficial, but they must be administered under close supervision⁽²⁾.

Fatigue. The prevalence of fatigue is up to 80% in people with multiple sclerosis. The etiology of fatigue is unclear, but there have been suggestions that disruption of neuronal networks, depression or psychological reactions, sleep disturbances, inflammation or medication may play a role in its development. Pharmacological and nonpharmacological strategies should be used in a treatment strategy⁽²⁾.

Nonpharmacological strategies include reviewing history for any possible contributing factors, the assessment and treatment of underlying depression if present, medication, pacing activities and appropriate exercise, and CBT⁽²⁾.

Pharmacological strategies include the use of amantadine or modafinil, but the efficacy remains unclear. Other pharmacological agents recommended include pemoline, aspirin and ginseng.

Epilepsy

People with epilepsy have an elevated prevalence of several psychiatric disorders, including depression (22.9%), anxiety (20.2%), psychosis (5.2%)⁽²⁾, cognitive dysfunction, mood lability, and impulsive behavior⁽¹⁾. Suicide is five-fold higher in epilepsy compared to the general population, and it is an important cause of premature mortality⁽²⁾. The link between epilepsy and mental illness is bidirectional, as patients with depression, anxiety and psychosis have an increased risk of developing new-onset epilepsy. Suicide attempts are also associated with the development of epilepsy. This bidirectional relationship might be explained by a common underlying pathology between mental illness and epilepsy. Disturbances in neurotransmission, neuroinflammation and in the HPA axis have all been suggested to be the shared pathology⁽²⁾.

Interictal psychiatric disorders (with symptoms occurring independently of seizures) are likely to require treatment with psychotropics. When prescribing psychotropics in people with epilepsy, the following general principles should be adhered to⁽²⁾:

1. Rule out other possible causes of psychiatric symptoms (both peri-ictal and iatrogenic).

2. Optimize the treatment of epilepsy (ideally, before prescribing psychotropics).

3. Consider using psychotropics with known antiseizure properties.

4. Check for interactions with anti-seizure medications.

5. Start with a low dose and titrate according to tolerability and response (proconvulsive effects are dose-related).

6. If seizures do occur, consider changing the psychotropic drug or optimizing the antiseizure medication⁽²⁾.

Peri-ictal psychiatric symptoms are temporally related to seizures. Depressive symptoms do not appear to respond to the treatment with antidepressants⁽²⁾.

Preictal psychiatric symptoms are typically present as a dysphoric mood preceding a seizure by a period of 30 minutes to two or three days⁽²⁾. All peri-ictal psychiatric symptoms (preictal, postictal and ictal) are initially treated by optimizing the anti-seizure medications⁽²⁾.

Postictal psychiatric symptoms are typically present between several hours to seven days following a seizure (depression, anxiety, suicidal ideation and psychosis reported). Epilepsy and interictal psychiatric disorders may experience the worsening of symptoms previously in remission (breakthrough symptoms). Postictal psychosis can remit spontaneously or respond to treatment with low doses of antipsychotics. Short-term symptomatic treatment with a benzodiazepine or an antipsychotic is recommended for up to three months. Taper off carefully after symptoms’ resolution⁽²⁾.

Ictal psychiatric symptoms may present as ictal fear/panic, depressive symptoms or, rarely, psychosis. There is no evidence that psychotropics can prevent ictal symptoms⁽²⁾.

Para-ictal episodes or forced normalization are psychiatric symptoms emerging as a result of a reduction in seizure frequency. They are psychotic or, less common, severe affective symptoms following seizure remission in epilepsy. Rapid medication titration schedules, rapid seizure control, previously medication-resistant epilepsy, and temporal lobe epilepsy may be risk factors⁽²⁾. Symptomatic treatment with antipsychotic or antidepressants may be indicated⁽²⁾.

Iatrogenic psychiatric symptoms are a result of changes in the treatment for seizures:

• starting antiseizure medications with known negative psychotropic properties (particularly in those with a psychiatric history);
• stopping anti-seizure medications with beneficial psychotropic properties (e.g., mood stabilization);
• starting antiseizure medications with enzyme-inducing properties in people stable on psychotropics;
• surgery for epilepsy – de novo postsurgical episodes of depression, anxiety and, rarely, psychosis have been reported. The exacerbation of the preexisting conditions is more common⁽²⁾.

Symptoms are managed by resolving the underlying cause in the first instance. Consider switching anti-seizure medications with known negative psychotropic properties to better tolerated anti-seizure medication. Anti-seizure medication can lower folate levels which may affect mood. Folate levels should be checked, and the low levels should be remedied if necessary. If changing anti-seizure medications is not suitable, antidepressants can be considered for iatrogenic depressive symptoms. Postsurgical neuropsychiatric symptoms may be successfully treated with psychotropics⁽²⁾.

Psychotropics in epilepsy

Antidepressants

• Low risk, good choices: SSRIs (the generally preferred are citalopram, escitalopram and sertraline), mirtazapine and duloxetine are recommended for epilepsy.
• Probably low risk, use with caution (limited evidence): agomelatine, reboxetine, vortioxetine.
• Moderate risk, care required: lithium, trazodone, venlafaxine.
• Higher risk, should be avoided (proconvulsive at therapeutic doses): amoxapine, bupropion, TCA.

Antipsychotics

• Low risk, good choices: amisulpride/sulpiride, aripiprazole, high-potency first-generation antipsychotics (haloperidol, flupentixol) and risperidone are recommended for epilepsy.
• Probably low risk, use with caution (limited evidence): cariprazine.
• Moderate risk, care required: olanzapine, quetiapine.
• Higher risk, care required (proconvulsive at therapeutic doses): clozapine.
• Higher risk, should be avoided (proconvulsive at therapeutic doses): low-potency first-generation antipsychotics (FGA), such as chlorpromazine, depot antipsychotics.

Drugs for ADHD

• Low risk: methylphenidate.
• Probably low risk, use with caution (limited evidence): amphetamines, atomoxetine.

Cognitive deficits. Cognitive deficits associated with epilepsy are common, and the most effective management depends on aggressive seizure control. Antiepileptic drugs with fewer cognitive side effects – specifically, lamotrigine and levetiracetam – are generally preferred. Untreated depression can manifest as cognitive impairment, and the treatment of comorbid depression can improve cognition. Acetylcholinesterase inhibitors have not been found to be effective for cognitive deficits in epilepsy. Memantine is not recommended due to the concern for increased seizure risk⁽¹⁾.

Depression. Depression is very common in patients with epilepsy, with a prevalence of up to 10 times higher than in the general population, with a threefold increased suicide risk. Usually, depressive symptoms that are acutely temporally related to seizure activity (either ictal or peri-ictal) are best managed with improved seizure control. Interictal depressive symptoms can be managed with SSRIs as first-line agents, because they have little effect on the seizure threshold. Conversely, bupropion and clomipramine are not recommended because of their risk of lowering the seizure threshold⁽¹⁾.

Mania. Mania is rare in patients with epilepsy, with the exception of patients who have undergone disease-modifying surgeries, specifically lobectomies. The use of mood-stabilizing antiepileptic medications, such as lamotrigine, valproate and carbamazepine, is considered the first-line treatment, with cautious use of lithium as a second-line agent due to its possible epileptogenic activity⁽¹⁾.

Anxiety. Anxiety can be present either as an ictal or peri-ictal symptom, or may evolve as a chronic symptom as a result of anticipatory anxiety about a recurrence of seizure activity. SSRIs are the first-line agents. Benzodiazepines can be useful, given their anxiolytic and anticonvulsant properties, but they require consideration regarding adverse motor and cognitive effects, and the potential for dependence or abuse⁽¹⁾.

Psychosis. Patients with epilepsy have an eightfold risk of psychosis. Psychosis in epilepsy is either ictal or postictal (psychosis closely linked to seizures), alternative psychosis (psychosis linked to seizure remission, also referred to as “forced normalization”), interictal psychosis (intermittent episodes of psychosis not associated with seizures), or iatrogenic psychosis (psychosis related to anticonvulsant drugs, most notoriously levetiracetam). Anticonvulsants are the primary treatment for ictal and postictal psychosis. The treatment of interictal psychosis includes both anticonvulsants and antipsychotics⁽¹⁾.

The management of psychiatric disorders in neurological diseases has special challenges that cannot be adequately addressed by either psychiatry or neurology alone. However, the literature on clinician-friendly recommendations on how to coordinate neurological and psychiatric care is limited⁽³⁾.

General principles of well-coordinated care of PDND include recommendations for both the primary team (usually neurology) and the consulting team (psychiatry). Primary teams should delineate a specific question, establish roles, and follow-up on the recommendations of the consulting team. Consultants should do their independent assessment, be organized and specific in their recommendations, and anticipate potential problems. One of the most important aspects to develop well-coordinated care is the establishment of clear, frank and, preferably, oral communication between the teams. Practical difficulties in the management of PDND include pharmacodynamic and pharmacokinetic interactions, as well as mutual dependency between psychiatry and neurology⁽³⁾.   

Corresponding author: Raluca Pretorian E-mail: pretorianraluca@yahoo.com