Depression

The true prevalence of depression in AD is controversial, with estimates up to 86%. One reason for the mixed findings lies in the different methods employed to assess depression in AD, such as family interviews and patient self-report. Some symptoms of depression are confounded with components of AD (e.g., concentration, energy, interest). The probability of depression in AD appears to be greater if there is a history of depression either in the patient or in the family. Table 8.7 suggests differences between the signs of depression and possibly confounding signs of dementia. Interestingly, there does not appear to be a clear relationship between depressive symptoms and severity of AD (Verkaik et al., 2007). Depression is associated with greater social and functional impairments in patients with AD (Starkstein et al., 2005), although others have not observed a correlation between depression and functional impairment (Landes, Sperry, and Strauss, 2005).

Table 8.7 Clinical Aspects Differentiating Dementia from Depression

Selective serotonin reuptake inhibitors (SSRIs) are the preferred mode of treatment for depression in AD. Although clinical trials are relatively few, sertraline and citalopram have been shown to be effective (Lyketsos et al., 2000).

Apathy

Apathy, defined as diminished motivation not attributable to decreased level of consciousness, cognitive impairment, or emotional distress, is among the most common behavioral changes noted in AD. Assessment of apathy in AD may be difficult because it may be unclear whether decreased activity is due to apathy or inability to perform activities. Consistent with expectations based on frontal-subcortical circuitry, apathy in AD has been shown to be associated with bilateral reductions in gray matter volume in the anterior cingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and putamen (Bruen et al., 2008). Apathy in AD is associated with greater functional and cognitive impairment (Landes et al., 2005) as well as lower quality of life (Hurt et al., 2008).

Aggression

Aggressive verbalizations and acts are common in AD. Reported prevalence rates range from 25% to 67%, and studies have indicated that verbal aggression is more common in men and in individuals with delusions or agitation (Eustace et al., 2001) and is associated with increased placement in skilled nursing facilities. Sertraline has been associated with a 38% response rate for the treatment of aggression and irritability in AD (Lanctot et al., 2002).

Psychosis

Prevalence rates of psychotic symptoms in AD range from 10% to 73%, with rates in clinical populations exceeding community-based samples. Interestingly, hallucinations and delusions are significantly less common among individuals with early-onset AD (Toyota et al., 2007). Once present, delusions recur or persist for several years in most patients with AD (Fig. 8.3). The presence of hallucinations is associated with increased placement in skilled nursing centers.

Fig. 8.3 Incidence of psychosis in patients with Alzheimer disease. AD, Alzheimer disease; FTD, frontotemporal dementia; HD, Huntington disease; NPI, Neuropsychiatric Inventory; PD, Parkinson disease; PSP, progressive supranuclear palsy.

(Reprinted with permission from Paulsen, J.S., Salmon, D.P., Thal, L.J., et al., 2000. Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology 54, 1965-1971.)

Previously it was believed that individuals with AD experienced delusions secondary to significant cognitive difficulties. However, more recent research has identified additional correlates and biological markers of psychosis. Evidence from neuropsychological investigations suggests more executive and frontal dysfunction in AD with psychotic symptoms than AD without these symptoms. For example, delusions have been associated with reduced gray matter volume in the inferior right frontal gyrus and the inferior parietal lobule (Bruen et al., 2008). The presence of delusions in AD is associated with poorer performance on the Frontal Assessment Battery (FAB) but was not related to global measures of cognitive impairment (i.e., MMSE) (Nagata et al., 2009). Persons with AD and hallucinations are at significantly increased risk for mortality; however, delusions alone are not associated with increased mortality (Wilson et al., 2005)

The most common psychotic symptoms reported in patients with AD are delusions and hallucinations. The delusions are typically paranoid-type, non-bizarre, and simple. Complex or bizarre delusions seen in patients with schizophrenia are conspicuously absent in patients with AD. Misidentification phenomena, however, are common in AD. Whereas hallucinations in AD are more often visual than auditory, the reverse is true for schizophrenia (Table 8.8).

Table 8.8 Psychotic Symptoms in Alzheimer Disease versus Schizophrenia in Elderly Patients

Reprinted with permission from Jeste, D.V., Finkel, S.I., 2000. Psychosis of Alzheimer’s disease and related dementias. Am J Geriatr Psychiatry 8, 29-34.

Behavioral Disruption

Atrophy within the frontal lobes leads to disruption of the frontosubcortical circuits and the characteristic behavioral syndromes in FTLD. Two classic behavioral syndromes have been described among individuals with FTD: an apathetic and a disinhibited subtype. Apathy is a very common symptom in individuals with FTD. Individuals may show little concern for personal hygiene and may appear unkempt. Moreover, symptoms of orbitofrontal syndrome, such as disinhibition, poor impulse control, tactlessness, and poor judgment are common. Loss of empathy, mental inflexibility, and stereotyped behaviors are also common. Symptoms similar to those observed in Klüver-Bucy syndrome, such as hyperorality and hypersexuality, may occur in late stages. Frequently the family members and caregivers are the ones who report these behavioral disturbances, as many patients with FTD experience reduced insight into their current difficulties. Behavioral change to varying degrees has been described in all FTLD syndromes, including SD and PNFA (Kertesz et al., 2010), although they frequently are less severe and/or occur later in the progression of the illness.

No curative treatments exist for FTLD. However, there has been some success with pharmacological intervention for behavioral dyscontrol. Although few large-scale studies have been completed, evidence suggests that behavioral disturbances such as disinhibition, overeating, and compulsions may show some response to treatment with SSRIs (Huey, Putnam, and Grafman, 2006).

Anosognosia

As noted in the consensus criteria, individuals with FTD frequently exhibit anosognosia. This loss of insight may reflect psychological denial of illness, inability to perceive symptoms, or lack of concern for their current difficulties. Among individuals with FTLD, individuals with bvFTD exhibit greater anosognosia than individuals with the aphasic subtypes of FTLD (Zamboni et al., 2010). Patients with FTD frequently describe significantly fewer problems with cognition and behavior than what their caregivers describe. Moreover, this observed discrepancy between patient and caregiver report is greater among individuals with FTD than in individuals with AD, particularly for language, behavior, and functioning difficulties (Salmon et al., 2008). Severity of anosognosia is not typically associated with severity of dementia (Zamboni et al., 2010). The relationship between impaired awareness and specific neuropathology is somewhat unclear. Some studies have shown an association between impaired awareness and right frontal disruptions (Mendez and Shapira, 2005) while others have shown a link between anosognosia and involvement of the right temporoparietal cortex (Zamboni et al., 2010).

Relationship to Primary Pathology

From a pathological perspective, individuals with FTLD vary with regard to the degree to which the frontal versus temporal lobes and right versus left hemispheres are affected. Significant research has looked at the relationship between patterns of behavioral syndromes and underlying neuropathology (see Josephs, 2007 for a review). Individuals with bvFTD typically exhibit greater frontal versus temporal atrophy, which is typically symmetrical. There is emerging evidence to suggest that individuals with bvFTD and primarily apathetic behavioral changes show greater frontal involvement, particularly right dorsolateral prefrontal cortex (Zamboni et al., 2008; Massimo et al., 2009). Individuals with primarily disinhibited behavioral change show greater involvement of the right mediotemporal limbic and temporal lobe (Zamboni et al., 2008), although others have described increased atrophy within the left dorsolateral prefrontal cortex (Massimo et al., 2009). Individuals with SD most typically exhibit atrophy and dysfunction within the left anterior temporal lobe, while individuals with SD and behavioral changes are more likely to also exhibit changes in the ventromedial and superior frontal lobes. Individuals with PNFA are most likely to show changes in left frontal and perisylvian areas.

Depression

The mean reported prevalence of depression in VaD is 32%, although rates vary widely between studies (Ballard and O’Brien, 2002). Sample source likely influences the reported prevalence rates, with community samples endorsing lower rates of depression than clinic samples. Individuals with VaD and depression are less likely to have had a stroke and are more likely to have a prior history of depression and impairments in memory or attention than patients with VaD without depression. The relationship between age and depression in VaD is unclear, with increased rates of depression being reported in both younger and older samples.

Additional Behavioral and Psychiatric Disorders

Apathy in VaD is associated with increased impairment in both basic and instrumental activities of daily living (Zawacki et al., 2002). This relationship is particularly apparent in patients with VaD who have also experienced a stroke. Rates of psychotic symptoms are similar in AD and VaD. Delusions (33%) and visual hallucinations (13% to 25%) are reported in VaD and are associated with impaired cognitive functioning (Ballard and O’Brien, 2002). Care must be taken in the assessment of delusions in VaD and in dementia in general. It is important to differentiate delusions from confabulation or thought processes based on impaired cognitive functioning.

Depression

Depression is the most common psychiatric disturbance in persons with PD. Depending on threshold for diagnosis and sample assessed, reported rates vary depending on the threshold for diagnosis of depression that is used. Depression may predate the onset of motor symptoms in PD (Ishihara and Brayne, 2006). Risk factors for depression in PD include greater cognitive impairment, earlier disease onset, and family history of depression. Depression is not associated with increased motor symptom severity (Holroyd et al., 2005). The correlation between depression and disability is equivocal. Although the precise etiology is unknown, it is believed that depression in PD results from disruptions in dopamine (D2), noradrenaline, and serotonin pathways (Veazey et al., 2005).

Very few well-controlled studies have assessed antidepressant therapy in PD. Available research suggests that SSRIs are well tolerated and likely effective in the treatment of depression in PD (see McDonald et al., 2003 for a review). SSRIs are frequently implemented as a first-line therapy for depression in patients with PD, although SSRIs may worsen motor symptoms. In such cases, tricyclic antidepressants may be an effective alternative. Successful treatment of depressive symptoms with an SSRI may also result in reductions in anxiety and decreased disability.

Psychosis

Hallucinations, typically visual, occur in up to 40% of patients with PD, with 16% reporting delusions (Fenelon et al., 2000). Psychotic symptoms are very uncommon early in the course of PD. Other diagnoses such as dementia with Lewy bodies (DLB) should be considered in patients exhibiting hallucinations early in the course of the disease. Table 8.10 summarizes important distinctions between psychosis in PD and DLB. Psychotic symptoms are more common in PD patients with greater cognitive impairment, longer duration of illness, greater daytime somnolence, and older age and in those who are institutionalized. Psychotic symptoms are strong predictors of nursing home placement and mortality in PD (Fenelon et al., 2000).

Table 8.10 Differentiating Psychosis in Parkinson Disease and Dementia with Lewy Bodies

DLB, Dementia with Lewy bodies; PD, Parkinson disease.

From Ismail, M.S., Richard, I.H., 2004. A reality test: how well do we understand psychosis in Parkinson’s disease? J Neuropsychiatry Clin Neurosci 16, 8–18. Copyright 2004 by American Psychiatric Press Inc. Reproduced with permission.

Historical accounts of PD rarely described psychotic symptoms, and it has been postulated that psychosis occurred secondary to dopamine agonist use. While dopamine agonists may contribute to the development of psychosis, additional factors are also important. For example, individuals with psychosis are more likely to exhibit cholinergic deficits and have Lewy bodies in the temporal lobe observed at autopsy (Aarsland et al., 2009).

Intervention for remediation of psychotic symptoms in PD can involve several processes. Discontinuation of anticholinergics, selegiline, and amantadine before reducing l-dopa is recommended. Following these discontinuations, reduction and simplification of dopamine agonists may be beneficial. Atypical antipsychotics are added only when a reduction of other medications has not resulted in improvement, as even atypical antipsychotics have been associated with worsening of PD motor symptoms (Goetz et al., 2000).

Apathy

Individuals with PD often experience increased rates of apathy. Estimates of apathy in PD have ranged from 16.5% to 40.0%. Individuals with apathy exhibit greater cognitive impairment (Dujardin et al., 2007). Controlled clinical trials for apathy in PD are very limited. Environmental and other behavioral interventions including establishment of a routine, structured schedule, and cuing from others can be helpful in some settings. Dopamine agonists, psychostimulants, modafinil, dopamine agonists, and testosterone have been reported to be helpful in decreasing apathy (see Aarsland et al., 2009 for more detailed information).

Psychosis

Psychotic symptoms, particularly hallucinations, are a hallmark feature of DLB. Insight is typically poor. Unlike patients with AD or PD, patients with DLB exhibit hallucinations early in the course of the illness. Delusions are also common in DLB. The neuropathological correlates of hallucinations in DLB are somewhat unclear. It has been suggested that hallucinations are likely due to decreased acetylcholine as well as changes in the basal forebrain and the ventral temporal lobe (Ferman and Boeve, 2007).

Hallucinations are correlated with poorer functioning with regard to instrumental activities of daily living (Ricci et al., 2009). Typical neuroleptics are avoided in DLB, because patients exhibit high sensitivity to these drugs and may experience severe parkinsonian symptoms and other side effects. In contrast, atypical neuroleptics such as clozapine and quetiapine, as well as cholinesterase inhibitors, are associated with improved cognition and decreased psychotic symptoms (McKeith, 2002).

Depression

Depression is one of the most common concerns for individuals and families with HD, occurring in up to 63% of patients. Depression may precede the onset of neurological symptoms in HD by 2 to 20 years, although large-scale empirical research has been minimal. Depression is common immediately before diagnosis, when neurological soft signs and other subtle abnormalities become evident. Following a definite diagnosis of HD, however, depression is most prevalent in the middle stages of the disease (i.e., Shoulson-Fahn stages 2 and 3) and may diminish in the later stages (Paulsen et al., 2005b). Positron emission tomography (PET) studies indicate that patients with HD with depression have hypermetabolism in the inferior frontal cortex and thalamus relative to nondepressed patients with HD or normal age-matched controls.

Suicide

Suicide is more common in HD than in other neurological disorders with high rates of depression such as stroke and PD. Most studies have found a four- to sixfold increase of suicide in HD, with reports as high as 8 to 20 times greater than the general population. Two “critical periods” during which suicidal ideation in HD increased dramatically have been identified. First, frequency of suicidal ideation doubles from 10.4% in at-risk persons with a normal neurological examination to 20.5% in at-risk persons with soft neurological signs. Second, in persons with a diagnosis of HD, 16% had suicidal ideation in stage 1, whereas nearly 21% had suicidal ideation in stage 2. Although the underlying mechanisms for suicidal risk in HD are poorly understood, it may be beneficial for healthcare providers to be aware of periods during which patients may be at an increased risk of suicide (Paulsen et al., 2005a).

Psychosis

Psychosis occurs with increased frequency in HD, with estimates ranging from 3% to 12%. Psychosis is more common among early adulthood-onset cases than among those whose disease begins in middle or late adulthood. Psychosis in HD is more resistant to treatment than psychosis in schizophrenia. Huntington Study Group data suggest that psychosis may increase as the disease progresses (see Table 8.11), although psychosis can become difficult to measure in the later stages of disease.

Obsessive-Compulsive Traits

Although true OCD is rare in HD, obsessive and compulsive behaviors are prevalent (13% to 30%). Obsessional thinking often increases with proximity to disease onset and then remains stable throughout the illness. Obsessional thinking associated with HD is reminiscent of perseveration, such that individuals get “stuck” on a previous occurrence or need and are unable to shift.

Aggression

Aggressive behaviors ranging from irritability to intermittent explosive disorders occur in 19% to 59% of patients with HD. Although aggressive outbursts are often the principal reason for admission to a psychiatric facility, research on the prevalence and incidence of irritability and aggressive outbursts in HD is sparse. The primary limitation in summarizing these symptoms in HD is the varied terminology used to describe this continuum of behaviors. Clinicians and HD family members suggested that difficulty with placement attributable to the patient’s aggression was among the principal obstacles to providing an effective continuum of care.

Apathy

Early signs of HD may include withdrawal from activities and friends, decline in personal appearance, lack of behavioral initiation, decreased spontaneous speech, and constriction of emotional expression. Frequently these symptoms are considered reflective of depression. Though difficult to distinguish, apathy is defined as diminished motivation not attributable to cognitive impairment, emotional distress, or decreased level of consciousness. Depression involves considerable emotional distress evidenced by tearfulness, sadness, anxiety, agitation, insomnia, anorexia, feelings of worthlessness and hopelessness, and recurrent thoughts of death. Both apathy (59%) and depression (70%) are common in HD. However, 53% of individuals experienced only one of these symptoms rather than the two combined. Furthermore, depression and apathy were not correlated.

Depression

Depression is the most common behavioral symptom in MS, occurring at rates of 37% to 54%. Patients with MS may report symptoms of depression even with outward signs of euphoria. While depression is frequently associated with reduced quality of life, the correlation between depressive symptoms and disability in MS is debated with equivocal research. Depression in MS is not consistently associated with increased rates of stressful events, disease duration, sex, age, or socioeconomic status. Among the subtypes of MS, depression may be most common in those with relapsing-remitting MS (Beiske et al., 2008). Fatigue is a strong predictor of depression among individuals with MS (Beiske et al., 2008).

Increased rates of suicidal ideation, suicide attempts, and completed suicides have been observed in individuals with MS. Suicide rates in MS are between two and seven times higher than in the general population (Bronnum-Hansen et al., 2005). Risk factors for suicidal ideation in MS include social isolation, current depression, and lifetime diagnosis of alcohol abuse disorder. Although suicide attempts occur throughout the progression of the disease, some have suggested that increased risk may be particularly high in the year following diagnosis (Bronnum-Hansen et al., 2005).

Biological factors likely contribute to depressive symptoms in MS. It has been hypothesized that the inflammatory process associated with MS may directly lead to depressive symptoms. Similarly, demyelination lesions in MS may directly contribute to the etiology of depression. Imaging studies in MS, however, have failed to show clear neuropathological correlates of depression. Disruptions have been observed in right parietal, right temporal, and right frontal areas (Zorzon et al., 2001) as well as the limbic cortex, implying disruption of frontosubcortical circuitry. It is likely that depression in MS results from a combination of psychosocial and biological factors.

Although controversial, depression may be a side effect for some individuals treated with interferon beta-1b (IFN-β-1b) (Feinstein, 2000). Patients with severe depression should be closely monitored while receiving IFN-β-1b. The relationship between depression and IFN-β-1a and interferon alfa (IFN-α) is equivocal, as conflicting results have been reported. In contrast, glatiramer acetate has not been associated with increased depressive symptoms (Feinstein, 2000). Because of the potential relationship between depression and treatment for MS, as well as the high rates of depression in MS, it is critical that physicians take care to thoroughly assess a patient’s current and past history of depression. This may be particularly important prior to beginning IFN interventions, as patients with histories of depression may be more likely to experience symptoms of depression following IFN treatment.

Few randomly assigned clinical trials have been conducted for the treatment of depression in MS. Several open-label trials of SSRIs have been conducted, which suggest that SSRIs may be effective in the treatment of depression in MS (Siegert and Abernethy, 2005). In addition, psychotherapy, particularly that focusing on coping skills, is efficacious in the reduction of depressive symptoms.

Anxiety

Although common, anxiety is often overlooked because anxiety symptoms may be viewed as a result of poor coping skills. Some strategies to minimize anxiety in individuals with MS are described in Box 8.2. Comorbid anxiety and depression are associated with greater somatic complaints, social difficulties, and suicidal ideation than either anxiety or depression alone. Predictors of anxiety in individuals with MS include fatigue, pain, and younger age of onset (Beiske et al., 2008).

Euphoria

Increased rates of cheerfulness, optimism, and denial of disability may occur in MS. Early studies suggested that over 70% of individuals with MS experienced periods of euphoria. However, more recent studies suggest that prevalence rates of euphoria are between 10% and 25%. Euphoria frequently co-occurs with disinhibition, impulsivity, and emotional liability. Individuals with euphoria are more likely to have cerebral involvement, enlarged ventricles, poorer cognitive and neurological function, and increased social disability.

Pathological Laughing and Crying

Pathological laughing and crying (PLC) occurs when there is disparity between an individual’s emotional experience and his or her emotional expression; affected individuals are unable to control laughter or crying. Approximately 10% of individuals with MS exhibit periods of PLC. (Parvizi et al., 2009). PLC is more common in MS patients who have entered the chronic-progressive disease course, have high levels of disability, and cognitive dysfunction. The neuropathological substrate for PLC is believed to involve several aspects of the frontosubcortical circuits as well as the cerebellum (Parvizi et al., 2009). Table 8.13 gives more detailed information. Dextromethorphan/quinidine may be effective in treating such symptoms (Panitch et al., 2006). Additionally, tricyclic and SSRI antidepressant medications may be helpful in reducing PLC symptoms (Parvizi et al., 2009).

Table 8.13 Neuroanatomical Structures and Pathological Laughing and Crying

Modified with permission from Parvizi, J., Coburn, K.L., Shillcutt, S.D., et al., 2009. Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research. J Neuropsychiatry. Clin Neurosci 21, 75-87. Copyright 2009, American Psychiatric Association.

Depression

Depressive symptoms occur in 40% to 50% of individuals with ALS (Kubler et al., 2005), although most individuals exhibit subsyndromal depression. Depression in ALS is associated with increased physical impairment, although these results are not always replicated. Individuals with low psychological well-being were at increased risk of mortality (Fig. 8.4). Mortality risk was more strongly associated with psychological distress than age and was similar to the association of risk associated with severity of illness. Depression is correlated with duration of illness; however, depression is not associated with ventilator use or tube feeding (Kubler et al., 2005).

Fig. 8.4 Poststroke survival by presence or absence of depression and executive dysfunction (endpoint, all causes of death). Note: determined by Kaplan Meier Logistic-Rank Analysis.

(Reprinted with permission from Melkas, S., Vataja R., Oksala N.K., et al., 2010. Depression-executive dysfunction syndrome relates to poor poststroke survival. Am J Geriatr Psychiatry 18, 1007-1016. Available at: http://dx.doi.org/10.1097/JGP.0b013e3181d695d7.)

Pathological Laughing and Crying

Up to 50% of individuals with ALS, most often those with pseudobulbar syndrome, report PLC (Parvizi et al., 2009). Individuals with PLC may be more likely to exhibit behavioral changes similar to those observed among individuals with FTD (Gibbons et al., 2008). Little research has assessed treatment of pseudobulbar affect. Potential pharmacological interventions include use of tricyclic and SSRI antidepressant medications (Parvizi et al., 2009). Dextromethorphan/quinidine may also be an effective treatment for PLC (Parvizi et al., 2009). Reduction in PLC symptoms was associated with improved quality of life and quality of relationships.

Personality Change

With recognition of the correlation between ALS and FTD, increased interest has been placed on assessing for potential behavioral changes in ALS. Minimal research has fully explored this question. Gibbons and colleagues (2008) assessed behavioral changes among a small group of individuals with ALS by using a structured interview of close family members of those with ALS. In this small study, 14/16 individuals with ALS exhibited behavioral changes. Of those with behavioral changes, 69% exhibited reduced concern for others, 63% exhibited increased irritability, and 38% exhibited increased apathy.

Depression

Depression is the most common psychiatric disorder in epilepsy. Rates of depression vary as a function of the sample assessed (clinical samples report higher rates of depression than population samples) and the measures used to diagnosis depression. Depression often goes undiagnosed in patients with epilepsy, because symptoms of depression may be viewed as a normal reaction to illness. However, accurate diagnosis of depression is critical because depression is associated with poorer quality of life, employment, and family functioning (Ettinger et al., 2004). Interestingly, presurgical depression is associated with poorer postsurgical seizure outcomes (Metternich et al., 2009).

Attempted and completed suicides are common in epilepsy. The suicide rate in epilepsy is two or more times greater than in the general population (Stefanello et al., 2010). Rates of suicide are even higher in temporal lobe epilepsy. Risk factors include history of self-harm, family history of suicide, stressful life situations, poor morale, stigma, and psychiatric disorders. Individuals with difficulties with comorbid anxiety and depression are at greater risk for suicidal ideation than individuals with only one syndrome (Stefanello et al., 2010).

The cause of depression in epilepsy is unclear. Psychosocial stressors, genetic disposition, and neuropathology may play contributing roles. Although psychosocial stressors have been suggested as important in the cause of depression in epilepsy, observed rates of depression in epilepsy are higher than those in other chronically ill patient populations, lending support to theories of biological causes. Perception of seizure control is an important psychosocial variable to consider, as a lower perception of seizure control is associated with increased depressive symptoms. Though results are somewhat mixed, there appears to be no relationship between age of onset or duration of epilepsy and depression. Depression appears to be more common in individuals with focal epilepsy than in those with primarily generalized epilepsy. Lateralization of seizure foci may be related to depression, with left-sided foci being more commonly associated with depression.

Pharmacological treatment of epilepsy may contribute to depression and psychiatric symptoms in general. Table 8.15 notes commonly used antiepileptic drugs and their psychotropic effects. Medications associated with sedation (e.g., barbiturates, benzodiazepines) may lead to depression, fatigue, and mental slowing.

Although the phenomenology of depression in epilepsy may prove dissimilar from that in patients with general depression, similar treatments are efficacious in the treatment of depression. Supportive psychotherapy may prove beneficial, particularly after initial diagnosis as patients begin to adapt to their illness. Few clinical trials have assessed the efficacy of antidepressant medications in patients with epilepsy. Older antidepressants and the antidepressant, bupropion, have been associated with increased seizures and thus should be avoided. Prueter and Norra (2005) suggest that citalopram and sertraline be considered first-line antidepressant medications in epilepsy because of their limited interactions with antiepileptic medication.

Anxiety

Increased rates of anxiety disorders occur in patients with epilepsy. Between 19% and 50% of individuals with epilepsy meet criteria for one or more DSM-IV anxiety disorder (Beyenburg et al., 2005). Individuals with comorbid anxiety and depressive disorders report lower quality of life than individuals with either disorder alone (Kanner et al., 2010). Common anxiety disorders include agoraphobia, generalized anxiety disorder, and social phobia. Fear of having a seizure and anticipatory anxiety are quite common. Care must be taken to distinguish between panic attacks and fear occurring in the context of a seizure (“ictal fear”). Fear is the most common psychiatric symptom to manifest during a seizure.

The relationship between antiepileptic drugs (AEDs) and anxiety is complex. Some AEDs appear to exacerbate anxiety symptoms, and others are associated with reduction in anxiety symptoms. Antidepressant medication, particularly the SSRIs, is the most common pharmacological treatment for anxiety in epilepsy. See the review by Beyenburg and colleagues (2005) for a more detailed discussion of treatment of anxiety in epilepsy.

Psychosis

The association between epilepsy and psychosis has been debated throughout the past century. Individuals with epilepsy onset before age 20 years, duration of illness greater than 10 years, history of complex partial seizures, and temporal lobe epilepsy are at increased risk of psychotic disturbances. Postictal and interictal psychosis are most commonly reported. Postictal psychosis most commonly develops after many years of epilepsy (Devinsky, 2003). Episodes of postictal psychosis are short in duration, lasting from a few hours to a few months. Postictal psychosis is more common with limbic lesions (Devinsky, 2003). In interictal psychosis, episodes of psychosis are not temporally tied to seizure onset and typically last for more than 6 months.

Aggression

The relationship between epilepsy and aggression remains controversial. Early research suggested that the prevalence of aggression in epilepsy ranged from 4.8% to 50.0%. Aggression occurring in the context of a seizure is quite rare (Devinsky, 2003). Rates of aggression are believed to be higher in individuals with temporal lobe epilepsy. Results vary owing to the definition of aggression used and the method of group selection. Interictal aggression may be described as episodic dyscontrol or, as in the DSM-IV nosology, intermittent explosive disorder (IED), which is characterized by periods of largely unprovoked anger, rage, severe aggression, and violent behavior. Hippocampal sclerosis is less common in individuals with epilepsy and aggression (Tebartz van Elst et al., 2000). A subgroup of individuals with epilepsy and aggression have significant amygdala atrophy (Tebartz van Elst, 2002).

Depression

Within the first year following a stroke, 30% to 40% of patients experience depression, with most developing depression within the first month (Ballard and O’Brien, 2002). Interestingly, rates appear to be similar for individuals in early, middle, and late stages following stroke. Depression after a stroke is associated with age, time since stroke, cognitive impairment, and social support. Significantly higher rates (5 to 6 times more likely) of poststroke depression have been reported among individuals with a premorbid diagnosis of depression (Ried et al., 2010).

Depression is associated with longer hospital stays, suggesting that it affects rehabilitation efforts. Depression is associated with poorer recovery of activities of daily living and increased morbidity. Depression and executive dysfunction commonly co-occur following a stroke. The presence of executive dysfunction with or without co-occurring depressive symptoms may be the strongest predictor of morbidity following stroke (Melkas et al., 2010) (see Fig. 8.4). Studies assessing the relationship between disability and depression in stroke patients have been equivocal. Depression is associated with poorer quality of life in individuals who have had a stroke, even when neurological symptoms and disability are held constant.

The relationship between depression and lesion location has been the focus of significant research and controversy. Early research by Robinson and Price showed that left anterior lesions were associated with increased rates and severity of depression. Lesions nearer the left frontal pole or left caudate nucleus were associated with increased rates of depression. Some researchers have replicated these findings, but others have failed to do so. More recent review articles have not supported a relationship between lesion location and depression in poststroke patients (Bhogal et al., 2004). Of note, there is significant heterogeneity in previous studies, particularly between different sample sources.

If more homogeneous groups of patients are considered, some relationships emerge. Depression is associated with left-sided lesions in studies using hospital samples, whereas depression is associated with right-sided lesions in community samples (Bhogal et al., 2004). Time since stroke is an additional important variable to consider. Poststroke depression is associated with left-sided lesions in individuals in the first month following stroke (Bhogal et al., 2004). However, poststroke depression is associated with right-sided lesions in individuals more than 6 months after the stroke (Bhogal et al., 2004). Other differences in previous research, such as method of depression diagnosis, may contribute to the mixed results.

Few studies have assessed the effectiveness of various treatments for depression in these patients. A recent review suggests that there is no clear evidence that standard antidepressant medications are effective in the treatment of poststroke depression (Hackett et al., 2005). Although such interventions may not lead to effective cessation of depressive disorders, they may result in overall reductions in depressive severity. One study suggests that nortriptyline was more effective in the treatment of depression than either placebo or fluoxetine (Robinson et al., 2000). In this study, response to treatment with nortriptyline was associated with improvement in cognitive and functional abilities. This improvement in cognition and functional abilities following reduction in depressive symptoms has not always been replicated (Hackett et al., 2005).

Pathological Laughing and Crying

A portion of individuals experience PLC after a stroke. Between 11% and 35% of individuals experience emotional incontinence after stroke (Parvizi et al., 2009). Emotional incontinence is associated with lesions of the brainstem and cerebellar lesions (see Parvizi et al., 2009 for a review). Research assessing treatment for PLC has been largely limited to case studies. Preliminary evidence suggests that tricyclic and SSRI antidepressants may be helpful in alleviating symptoms of PLC (Parvizi et al., 2009).

Aggression

Reports have suggested that individuals have difficulty controlling aggression and anger following a stroke. Inability to control anger or aggression was associated with increased motor dysfunction and dysarthria. Aggression following stroke is associated with increased rates of MDD and generalized anxiety disorder. There is some evidence that lesions in the area supplied by the subcortical middle cerebral artery are associated with inability to control anger or aggression. Poststroke irritability and aggression are associated with lesions nearer to the frontal pole. Fluoxetine has been shown to successfully reduce levels of poststroke anger (Choi-Kwon et al., 2006). Similarly, reductions in irritability and aggression have been associated with reductions in depression following pharmacological intervention (Chan et al., 2006).

Anosognosia

Although TBI is often associated with changes in motor, cognitive, and behavioral functioning, individuals with TBI frequently do not accurately assess these changes. Impairments in awareness have been associated with functional outcomes. Although it is most commonly reported that individuals with TBI underreport their difficulties, a subgroup of individuals appear to overreport their difficulties. It has been reported that individuals with mild to moderate TBI report greater impairments than their family members do of them, whereas those with more severe TBI report less impairments than their family member. Overreporting may be associated with depressive symptoms or litigation. Discussion of behavioral change following mild TBI is beyond the scope of the current discussion. Although symptoms of TBI frequently lead to difficulties in independent living and in the workplace, accurate assessment of these difficulties serves to mitigate this relationship. Thus, it is possible that improved levels of awareness may lead to reductions in disability.

Depression

Depression following TBI is common. Diagnosis of depression in TBI is complicated, because symptoms of depression (e.g., fatigue, concentration difficulties, sleep disturbances) are common following TBI. For further discussion regarding the diagnosis of depression in TBI, see Seel and colleagues (2010). MDD occurs in up to 60% of individuals who have suffered TBI (Kim et al., 2007). Rates of depression in TBI vary as a function of severity of TBI assessed, method of depression diagnosis, and sample source. The best predictor of depression after TBI is the presence of premorbid depression; however, some have failed to replicate this finding. Other factors associated with post-TBI depression include poor coping styles, social isolation, and increased stress (Kim et al., 2007). Depression in TBI is associated with increased suicidality, increased cognitive problems, greater disability, and aggression. See Table 8.17 for additional information regarding differentiating features associated with depression in TBI.

Suicidal ideation (65%) and attempts (8.1%) are common following TBI (Silver et al., 2001). In contrast to sex differences reported in the general population, women with TBI are more likely to commit suicide than men with TBI. Furthermore, suicide was more common in individuals with more severe injury and those younger than 21 years or older than 60 years at the time of injury.

No large class I studies of use of antidepressant medications, particularly SSRIs, in TBI have been completed, but small studies provide preliminary support for their use to treat depressive symptoms following TBI. Care must be taken in certain situations, because some antidepressants (i.e., bupropion) are associated with increased risk of seizures. Close monitoring following the beginning of a trial of antidepressant medication is encouraged; in some settings, such medications can increase agitation or anxiety in individuals with TBI. Please see Alderfer and colleagues (2005) for more details regarding recommendations for treatment of depression following TBI.

Anxiety

Less research has assessed the prevalence of anxiety disorders in TBI; however, studies suggest that 11% to 70% of individuals meet criteria for anxiety. A meta-analysis suggested that the mean prevalence of anxiety disorders following TBI is 29%. Panic disorder occurs in 3.2% to 9.0% of individuals with a TBI (Silver et al., 2001).

Apathy

Symptoms of apathy are reported in 10% to 60% of individuals with a TBI. Among individuals with TBI referred to a behavioral management program, lack of initiation was among the most common reported problems, occurring in approximately 60% of the sample (Kelly et al., 2008). Apathy in TBI is associated with depressive symptoms, although a significant number of individuals (28%) report experiencing apathy but not depression. Lesions affecting the right hemisphere and subcortical regions are more strongly associated with apathy than lesions affecting the left hemisphere.

Personality Change

Personality changes following TBI is common secondary to frequent injury to the frontal lobe and disruption of the frontosubcortical circuitry. Common changes include increased irritability, aggression, disinhibition, and inappropriate behavior. Although these difficulties can be among the most disabling for individuals with TBI, research in these areas is limited, and no uniform, agreed-upon diagnostic criteria for these behavioral changes exist.

Aggression within 6 months of TBI has been reported in up to 60% of individuals with TBI (Baguley et al., 2006). Among individuals referred to a TBI behavior management service, verbal aggression along with inappropriate social behavior were among the most commonly reported behavioral difficulties and occurred in more than 80% of individuals (Kelly et al., 2008). Aggression following TBI is associated with onset of depression following TBI, poorer psychosocial functioning, and greater disability (Rao et al., 2009).

A number of pharmacological interventions have been used to reduce and remediate behavioral changes following brain injury. See Nicholl and LaFrance (2009) for a review. One class of medication used in these settings is AEDs, now routinely used to treat aggression, disinhibition, and mania following TBI. Again, few large-scale studies have assessed the effectiveness of AEDs in the treatment of behavioral change following TBI. Historically, neuroleptic drugs were used in high doses to treat behavioral dyscontrol in individuals with cognitive impairment. More recently, there has been increased interest in the use of atypical neuroleptics to treat both psychosis and behavioral changes following TBI.

In addition to pharmacological interventions, behavioral and environmental interventions have been shown to be effective at remediating behavioral dyscontrol following TBI. The discussion of behavioral and environmental techniques aimed at decreasing behavioral dyscontrol, including aggression and irritability, is beyond the scope of this chapter (see Sohlberg and Mateer, 2001 for more information). Providers may find referrals for such interventions within rehabilitation programs. Briefly, interventions may seek to reduce stimulation in the environment, increase structure and predictability, reinforce good behavior with limited response to undesired behavior, and use of structured problem-solving strategies.