Principles of Differential Diagnosis

Emotional and cognitive processes are based on brain structure and physiology. Abnormal behavior can be attributable to the complex interplay of social influences, physical environment, and neural physiology. Psychosis, mania, depression, disinhibition, obsessive compulsive disorder (OCD), and anxiety all can occur as a result of neurological disease and can be indistinguishable from the idiopathic forms (Robinson and Travella, 1996). Neurological conditions must be considered in the differential diagnosis of any disorder with psychiatric symptoms.

Neuropsychiatric dysfunction can be correlated with altered functioning in anatomical regions. Any disease, toxin, drug, or process that affects a particular region can be expected to show changes in behavior mediated by the circuits within that region. The limbic system and the frontosubcortical circuits are most commonly involved in neuropsychiatric dysfunction. This neuroanatomical conceptual framework can provide useful information for localization and thus differential diagnosis. Klüver-Bucy syndrome, which consists of placidity, apathy, visual and auditory agnosia, hyperorality, and hypersexuality, occurs in processes that cause injury to the bilateral medial temporoamygdalar regions. A few of the most common causes of this syndrome include herpes encephalitis, traumatic brain injury (TBI), frontotemporal dementias (FTDs), and late-onset or severe Alzheimer disease (AD). Brain trauma, ischemic disease, demyelination, abscesses, or tumors, as well as degenerative dementias can also result in disinhibition. Damage to any portion of the circuit between the orbitofrontal cortex, ventral caudate nucleus, anterior globus pallidus, or mediodorsal thalamus can result in disinhibition (Tekin and Cummings, 2002).

Mood disorders, paranoia, disinhibition, and apathy derive from dysfunction in the limbic system and basal ganglia, which are phylogenetically more primitive (Mesulam, 2000). In some cases, the behavioral changes represent a response to the underlying disability; in others, behavioral abnormalities are part of the disease. For example, studies have shown that apathy in Parkinson disease (PD) is probably related to the underlying disease process, rather than being a psychological reaction to disability or to depression, and is closely associated with cognitive impairment (Kirsch-Darrow et al., 2006). Positron emission tomographic (PET) and single-photon emission computed tomographic (SPECT) studies suggest similar regions of abnormality in acquired forms of depression, mania, OCD, and psychosis, compared with their primary psychiatric presentations (Hirono et al., 1998; Rubinsztein et al., 2001; Saxena et al., 1998). Table 9.1 summarizes neuropsychiatric symptoms and their anatomical correlates. Additionally, the developmental phase during which a neurological illness occurs influences the frequency with which some neuropsychiatric syndromes are manifested. Adults with post-TBI sequelae tend to exhibit a higher rate of depression and anxiety. In contrast, post-TBI sequelae in children often involve attention deficits, hyperactivity, irritability, aggressiveness, and oppositional behavior (Geraldina et al., 2003). When temporal lobe epilepsy or Huntington disease (HD) begins in adolescence, a higher incidence of psychosis is noted than when their onset occurs later in life. Earlier onset of multiple sclerosis (MS) and stroke are associated with a higher incidence of depression (Rickards, 2005).

Table 9.1 Neuropsychiatric Symptoms and Corresponding Neuroanatomy

OCD, Obsessive-compulsive disorder.

Patients with AD, PD, HD, and FTDs can develop multiple coexisting symptoms such as irritability, agitation, impulse-control disorders, apathy, depression, delusions, and psychosis that may be exacerbated by medications used to treat the underlying disorder (Table 9.2). For example, in patients with PD dopamine agonists such as pramipexole and ropinirole have been found to increase the risk of pathological gambling, compulsive shopping, hypersexuality, and other impulse-control disorders, sometimes referred to as dopamine dysregulation (Voon et al., 2006; Weintraub et al., 2006). Management outcome can be influenced by multiple factors. For instance, the complex relationship between behavioral changes and the caregiver’s ability to cope play a role in illness management and nursing home placement (de Vugt et al., 2005; Smith et al., 2001). Behavioral disturbances in patients with neurological illness have been related to the severity of caregiver distress (Kaufer et al., 1998).

Table 9.2 Neurological Disorders and Associated Prominent Behavioral Features

ALS, Amyotrophic lateral selerosis; FTD, frontotemporal dementia; HD, Huntington disease; HIV, human immunodeficiency virus; MS, multiple sclerosis; OCD, obsessive-compulsive disorder; PSP, progressive supranuclear palsy; RBD, rapid eye movement behavior disorder; TBI, traumatic brain injury.

Principles of Neuropsychiatric Evaluation

A number of important principles must be taken into account when evaluating and treating a patient for behavioral disturbances.

The medical evaluation of affective illness and psychotic disorders must be individualized based on the patient’s family history, social environment, habits, risk factors, age, gender, clinical history, and examination findings. A careful review of the patient’s medical history and a general physical examination as well as a neurological examination (Murray and Price, 2008; Ovsiew et al., 2008) should be performed to assess for possible neurological and medical causes. The most basic evaluation should include vital signs (blood pressure, pulse, respirations, and temperature) and a laboratory evaluation that minimally includes a complete blood cell count (CBC); electrolyte panel; determination of serum levels for glucose, blood urea nitrogen (BUN), creatinine, calcium, total protein, and albumin; liver function assessment; thyroid function assessment; and additional laboratory testing as clinically indicated. Consideration should be given to checking the patient’s oxygen saturation on room air (especially in the elderly). Neurological abnormalities suggested by the clinical history or identified on examination, especially those attributable to the central nervous system (CNS), should prompt further evaluation for neurological and medical causes of psychiatric illness. A clear consensus has not been reached about when neuroimaging is indicated as part of the evaluation of new-onset depression in patients without focal neurological complaints and a normal neurological examination. This must be individualized based on clinical judgment. Treatment-resistant depression should prompt reassessment of the diagnosis and evaluation to rule out secondary causes of depressive illness. A careful history to rule out a primary sleep disorder such as sleep apnea should be considered in the evaluation of refractory depressive symptoms (Haba-Rubio, 2005) or cognitive complaints. When new-onset psychosis presents in the absence of identifiable infectious/inflammatory, metabolic, toxic, or other causes, we recommend that magnetic resonance imaging (MRI) of the brain be incorporated into the evaluation. In our experience, 5% to 10% of such patients have MRI abnormalities that identify potential neurological contributions (particularly in those 65 years of age and older). The MRI will help exclude lesions (e.g., demyelination, ischemic disease, neoplasm, congenital structural abnormalities, evidence of metabolic storage diseases) in limbic, paralimbic, and frontal regions, which may not be associated with neurological abnormalities on elemental examination (Walterfang et al., 2005). An electroencephalogram (EEG) should be considered to evaluate for complex partial seizures if there is a history of intermittent, discrete, or abrupt episodes of psychiatric dysfunction (e.g., confusion, spells of lost time, psychotic symptoms), stereotypy of hallucinations, automatisms (e.g., lip smacking, repetitive movements) associated with episodes of psychiatric dysfunction (or confusion), or a suspicion of encephalopathy (or delirium). Sensitivity of the EEG for detecting seizure activity is highest when the patient has experienced the specific symptoms while undergoing the study. Selected cases may require 24-hour or longer EEG monitoring to capture a clinical event to clarify whether a seizure disorder is present.

Cognitive-Behavioral Neuroanatomy

We begin with a brief overview of cortical functional anatomy and perceptual, cognitive, and behavioral processing, after which will follow a synopsis of frontal lobe functional anatomy describing the distinct frontosubcortical circuits subserving important cognitive-behavioral domains.

The cerebral cortex can be subdivided into five major functional subtypes: primary sensory-motor, unimodal association, heteromodal association, paralimbic, and limbic. The primary sensory areas are the point of entry for sensory information into the cortical circuitry. The primary motor cortex conveys complex motor programs to motor neurons in the brainstem and spinal cord. Processing of sensory information occurs as information moves from primary sensory areas to adjacent unimodal association areas. The unimodal and heteromodal cortices are involved in perceptual processing and motor planning. The complexity of processing increases as information is then transmitted to heteromodal association areas which receive input from more than one sensory modality. Examples of heteromodal association cortex include prefrontal cortex, posterior parietal cortex, parts of the lateral temporal cortex, and portions of the parahippocampal gyrus. These cortical regions have a six-layered architecture. Further cortical processing occurs in areas designated as paralimbic. These regions demonstrate a gradual transition of cortical architecture from the six-layered to the more primitive and simplified allocortex of limbic structures. The paralimbic regions consist of orbitofrontal cortex, insula, temporal pole, parahippocampal cortex, and cingulate cortex. Cognitive, emotional, and visceral inputs merge in these regions. The limbic subdivision is composed of the hippocampus, amygdala, substantia innominata, prepiriform olfactory cortex, and septal area (Figs. 9.1 and 9.2). These structures are to a great extent reciprocally interconnected with the hypothalamus. The limbic region is intimately involved with regulation of emotion, memory, motivation, autonomic, and endocrine function. The highest level of cognitive processing occurs in regions referred to as transmodal areas. These areas are composed of heteromodal, paralimbic, and limbic regions, which are collectively linked, in parallel, to other transmodal regions. Interconnections among transmodal areas (e.g., Wernicke area, posterior parietal cortex, hippocampal-enterorhinal complex) allow integration of distributed perceptual processing systems, resulting in perceptual recognition such as scenes and events becoming experiences and words taking on meaning (Mesulam, 2000).

Fig. 9.1 Cortical anatomy and functional subtypes (areas) described by Brodmann’s map of the human brain. The boundaries are not intended to be precise. Much of this information is based on experimental evidence obtained from laboratory animals and needs to be confirmed in the human brain. AA, Auditory association cortex; ag, angular gyrus; A1, primary auditory cortex; B, Broca area; cg, cingulate gyrus; f, fusiform gyrus; FEF, frontal eye fields; ins, insula; ipl, inferior parietal lobule; it, inferior temporal gyrus; MA, motor association cortex; mpo, medial parietooccipital area; mt, middle temporal gyrus; M1, primary motor area; of, orbitofrontal region; pc, prefrontal cortex; ph, parahippocampal region; po, parolfactory area; ps, peristriate cortex; rs, retrosplenial area; SA, somatosensory association cortex; sg, supramarginal gyrus; spl, superior parietal lobule; st, superior temporal gyrus; S1, primary somatosensory area; tp, temporopolar cortex; VA, visual association cortex; V1, primary visual cortex; W, Wernicke area.

(From Mesulam, M.M., 2000. Behavioral neuroanatomy. Large-scale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In: Mesulam, M.M. (Ed.), Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, p. 13.)

Fig. 9.2 Coronal section through the basal forebrain of a 25-year-old human brain stained for myelin. The substantia innominata (si) and the amygdaloid complex (a) are located on the undersurface of the brain. c, Head of caudate nucleus; cg, cingulate gyrus; g, globus pallidus; I, insula.

(From Mesulam, M.M., 2000. Behavioral neuroanatomy. Large-scale networks, association cortex, frontal syndromes, the limbic system and hemisphere specializations. In: Mesulam, M.M. (Ed.), Principles of Behavioral and Cognitive Neurology. Oxford University Press, New York, p. 4.)

Cortical Networks

Five distinct cortical network regions govern various aspects of cognitive functioning: (1) the language network, which includes transmodal regions or “epicenters” in Broca and Wernicke areas; (2) spatial awareness, based in transmodal regions in the frontal eye fields and posterior parietal area; (3) the memory and emotional network, located in the hippocampal-enterorhinal region and amygdala; (4) the executive function–working memory network, based in transmodal regions in the lateral prefrontal cortex and possibly the inferior parietal cortices; and (5) the face-object recognition network, based in the temporopolar and midtemporal cortices (Mesulam, 1998).

Lesions of transmodal cortical areas result in global impairments such as hemineglect, anosognosia, amnesia, and multimodal anomia. Disconnection of transmodal regions from a specific unimodal input will result in selective perceptual impairments such as category-specific anomias, prosopagnosia, pure word deafness, or pure word blindness.

The ability to empathize with another person’s psychological and physical circumstances is a foundation for social and moral behavior. The human mirror neuron system is now postulated to be involved in understanding the actions of others and the intentions behind the actions. It also may provide the basis for observational learning. The parietofrontal mirror system, which includes the parietal lobe and the premotor cortex plus the caudal part of the inferior frontal gyrus, is involved in recognition of voluntary behavior in other people, while the limbic mirror system, formed by the insula and the anterior mesial frontal cortex, is devoted to the recognition of affective behavior. Dysfunction of this system is postulated to underlie deficits in theory of mind and has been proposed as an explanation for the social deficits seen in autistic disorders (Cattaneo and Rizzolatti, 2009).

Frontosubcortical Networks

Five frontosubcortical circuits subserve cognition, behavior, and movement. Disruption of these networks at the cortical or subcortical level can be associated with similar neuropsychiatric symptoms. Each of these circuits shares the same components: (1) frontal cortex, (2) striatum (caudate, putamen, ventral striatum), (3) globus pallidus and substantia nigra, and (4) thalamus (which then projects back to frontal cortex) (Tekin and Cummings, 2002) (Fig. 9.3). Integrative connections also occur to and from other subcortical and distant cortical regions related to each circuit. Neurotransmitters such as dopamine (DA), glutamate, γ-aminobutyric acid (GABA), acetylcholine, norepinephrine, and serotonin are involved in various aspects of neural transmission and modulation in these circuits. The frontosubcortical networks are named according to their site of origin or function. Somatic motor function is subserved by the motor circuit originating in the supplementary motor area. Oculomotor function is governed by the oculomotor circuit originating in the frontal eye fields. Three of the five circuits are intimately involved in cognitive and behavioral changes: the dorsolateral prefrontal, the orbitofrontal, and the anterior cingulate circuits. Each circuit has both efferent and afferent connections with adjacent and distant cortical regions. The dorsolateral prefrontal circuit governs executive functions, including the ability to plan and maintain attention, problem solve, learn, retrieve remote memories, sequence the temporal order of events, shift cognitive and behavioral sets, and generate motor programs. Executive dysfunction is a principal component of subcortical dementias. Deficits identified in subcortical dementias include slowed information processing, memory retrieval deficits, mood and behavioral changes, gait disturbance, dysarthria, and other motor impairments. Vascular dementias, PD, and HD are a few examples of conditions that affect this circuit.

Fig. 9.3 General structure of frontal subcortical circuits.

The orbitofrontal circuit connects frontal monitoring functions to the limbic system. This circuit governs appropriate responses to social cues, empathy, social judgment, and interpersonal sensitivity. It pairs thoughts, memories, and experiences with corresponding visceral and emotional states. This circuit is heavily involved in the process of decision making and evaluating the costs and benefits of specific behavioral responses to the environment. The medial orbitofrontal cortex (OFC) evaluates reward, whereas the lateral OFC monitors and decodes punishment as it pertains to motivating behavioral change. There is also an anterior-posterior gradient in which the reward value for more abstract and complex secondary reinforcing factors such as money are encoded in the anterior regions, and more concrete factors such as touch and taste are encoded in the posterior OFC areas. The posterior OFC is thought to have an important role in evaluating the emotional significance of stimuli (Barbas and Zikopoulos, 2007). Dysfunction in this circuit can lead to disinhibition, irritability, aggressive outbursts, inappropriate social responses, and impulsive decision making. Patients with OFC lesions show deficits in both the production and recognition of emotional expression from the face, voice, or gestures. Persons with bilateral OFC lesions may manifest “theory of mind” deficits. Theory of mind is a model of how a person understands and infers other people’s intentions, desires, mental states, and emotions (Bodden et al., 2010). Conditions that exhibit impairment in this circuit include schizophrenia (Bora et al., 2009), FTD (Adenzato et al., 2010), and HD. Other conditions that may affect this circuit include closed head trauma, rupture of anterior communicating aneurysms, and subfrontal meningiomas.

The anterior cingulate circuit includes the nucleus accumbens and has both afferent and efferent connections to the dorsolateral prefrontal cortex (DLPFC) and amygdala. It is involved in motivated behavior. Lesions in this circuit result in apathy, abulia, and akinetic mutism. There also is a reported decrease in the ability to understand new thoughts and participate in the creative thought process (Chow and Cummings, 1999; Mesulam, 2000). The medial prefrontal cortex is thought to play a significant role in generating emotions related to empathy, cognitive functions related to theory of mind, and the ability to recognize a moral dilemma (Robertson et al., 2007). The ventromedial frontal lobe evaluates the current relative value of stimuli helping to guide decision making by determining the goals toward which behavior is directed and through judging outcomes (Fellows, 2007). Some conditions that may affect this circuit include AD, FTD, PD, HD, head trauma, brain tumors, cerebral infarcts, and obstructive hydrocephalus.

Cerebrocerebellar Networks

The cerebellum is engaged in the regulation of cognition and emotion through a feed-forward and feedback loop. The cortex projects to pontine nuclei, which in turn project to the cerebellum. The cerebellum projects to the thalamus, which then projects back to the cortex. Cognitive processing tasks such as language, working memory, and spatial and executive tasks appear to activate the posterior cerebellar lobe. The posterior cerebellar vermis may function as a putative limbic cerebellum, modulating emotional processing (Stoodley and Schmahmann, 2010). Distractibility, executive and working memory problems, impaired judgment, reduced verbal fluency, disinhibition, irritability, anxiety, emotional lability or blunting, obsessive compulsive behaviors, depression, and psychosis have been reported in association with cerebellar pathology.

Biology of Psychosis

Among several etiological hypotheses for schizophrenia, the neurodevelopmental model is one of the most prominent. This model generally posits that schizophrenia results from processes that begin long before the onset of clinical symptoms and is caused by a combination of environmental and genetic factors (Murray and Lewis, 1987; Weinberger, 1987). Several postmortem and neuroimaging studies support this hypothesis with findings of brain developmental alterations such as agenesis of the corpus callosum, arachnoid cysts, and other abnormalities in a significant number of schizophrenic patients (Hallak et al., 2007; Kuloglu et al., 2008). Environmental factors are associated with an increased risk for schizophrenia. These factors include being a first-generation immigrant or the child of a first-generation immigrant, urban living, drug use, head injury, prenatal infection, maternal malnutrition, obstetrical complications during delivery, and winter birth (Tandon et al., 2008). Genetic risks are clearly present but not well understood. The majority of patients with schizophrenia lack a family history of the disorder. The population lifetime risk for schizophrenia is 1%, 10% for first-degree relatives, and 4% for second-degree relatives. There is an approximately 50% concordance rate for monozygotic twins, compared to approximately 15% for dizygotic twins. Advancing paternal age increases risk in a linear fashion, which is consistent with the hypothesis that de novo mutations contribute to the genetic risk for schizophrenia. It is most likely that many different genes make small but important contributions to susceptibility. The disease only manifests when these genes are combined or certain environmental factors are present. A number of susceptibility genes show association with schizophrenia: catechol-O-methyl-transferase, neuroregulin 1, dysbindin, disrupted in schizophrenia 1 (DISC1), metabotropic glutamate receptor type 3 gene and G27/G30 gene complex (Nöthen et al., 2010; Tandon et al., 2008). Research in twins and first-degree relatives of patients has shown that genes predisposing to schizophrenia and related disorders affect heritable traits related to the illness. Such traits include neurocognitive functioning, structural MRI brain volume measures, neurophysiological informational processing traits, and sensitivity to stress (van Os and Kapur, 2009). A small proportion of schizophrenia incidence may be explained by genomic structural variations known as copy number variants (CNVs). CNVs consist of inherited or de novo small duplications, deletions, or inversions in genes or regulatory regions. CNV deletions generally show higher penetrance (more severe phenotype) than duplications, and larger CNVs often have higher penetrance and/or more clinical features than smaller CNVs. These genomic structural variations contribute to normal variability, disease risk, and developmental anomalies, as well as act as a major mutational mechanism in evolution. The most common CNV disorder, 22q11.2 deletion syndrome (velocardiofacial syndrome), has an established association with schizophrenia. Individuals with 22q11.2 deletions have a 20-fold increased risk for schizophrenia and constitute about 0.9% to 1% of schizophrenia patients. When this syndrome is present, genetic counseling is helpful (Bassett and Chow, 2008).

A wide variety of neurological conditions, medications, and toxins are associated with psychosis. No consensus is available in the literature regarding the precise anatomical localization of various psychotic syndromes. Evidence from neurochemistry, cellular neuropathology, and neuroimaging studies support that schizophrenia is a brain disease, but there is no universally accepted theory regarding the specific nature of the brain dysfunction. The two best-known neurotransmitter models offered to explain the various manifestations of schizophrenia include the “dopamine hypothesis,” now in its third revision (Howes and Kapur, 2009), and the “glutamate hypothesis.” Schizophrenia has been associated with frontal lobe dysfunction and abnormal regulation of subcortical DA (Goldman-Rakic et al., 2004) and glutamate systems (Weinberger, 2005).

Functional imaging studies in persons with schizophrenia show decreased cerebral blood flow (CBF) in the DLPFC during specific cognitive tasks (Andreasen, 1996; Lehrer et al., 2005). Schizophrenic patients with prominent negative symptoms display reduced glucose utilization in the frontal lobes. Functional imaging studies suggest that disruption in distributed functional circuits is important in the development of schizophrenia. These functional circuit locations include the DLPFC, orbitofrontal cortex, mediofrontal cortex, anterior cingulate gyrus, thalamus, temporal lobe subregions, and the cerebellum (Schultz and Andreasen, 1999). Several conditions that may manifest psychosis (e.g., HD, PD, frontotemporal degenerations, stroke) are commonly associated with frontal and subcortical dysfunction. Dorsolateral and mediofrontal hypoperfusion on functional imaging has been demonstrated in a subset of AD patients with delusions (Hirono et al., 1998).

Biology of Depression

The connection between psychiatry and neurology is nowhere more evident than the remarkable comorbidity of psychiatric illness, especially depression, in many neurological disorders, with a 20% to 60% prevalence rate of depression in patients with stroke, neurodegenerative diseases, MS, headache, human immunodeficiency virus (HIV), TBI, epilepsy, chronic pain, obstructive sleep apnea, intracranial neoplasms, and motor neuron disease. Depression amplifies the physiological response to pain, while pain-related symptoms and limitations frequently lead to the emergence of depressive symptoms. In a community-based study, almost 50% of adolescents with chronic daily headaches had at least one psychiatric disorder, most commonly major depression and panic. Women with migraine who have major depression are twice as likely as those with migraine alone to report being sexually abused as a child. If the abuse continued past age 12, women with migraine were five times more likely to report depression (Tietjen et al., 2007). Despite the proliferation of antidepressant therapeutics, major depression is often a chronic and/or recurrent condition that remains difficult to treat. Up to 70% of patients taking antidepressants in a primary care setting may be poorly compliant, most often due to adverse side effects during both short and long-term therapy.

Efforts to link single genes to major depressive disorder (MDD) have been unsuccessful despite exhaustive mapping attempts. Consequently, behavioral geneticists have turned to the study of genetic polymorphisms in establishing a predisposition to depression and in shaping the response to environmental stressors. Perlis and coworkers (2007) found a strong association between variation at the CREB1 locus and anger expression in MDD. The most extensive studies in this field have focused on polymorphisms in the serotonin transporter (5-HTT) gene. Recent work has demonstrated that patients with a single nucleotide polymorphism on the long allele that entails an A-to-G transposition (LG) have low expression of 5-HT. The risk for major depression among hurricane survivors with either short or LG alleles was four to five times that of low-risk survivors. Although conflicting results have been reported with regard to these polymorphisms, a recent meta-analysis found that the 44bp Ins/Del short/long polymorphism was associated with MDD, whereas the VNTR intron 2 polymorphism was not. This study also reported significant associations for polymorphisms in the apolipoprotein E, guanine nucleotide binding protein, methylenetetrahydrofolate reductase, and dopamine transporter genes (López-León et al., 2008).

Behavioral genetics research based on diathesis-stress models of depression demonstrate that the risk of depression after a stressful event is enhanced in populations carrying genetic risk factors and is diminished in populations lacking such risk factors. A gene’s contribution to depression may be missed in studies that do not account for environmental interactions and may only be revealed when studied within the context of environmental stressors specifically mediated by that gene (Uher, 2008). Genotype-environment interactions are ubiquitous because genes not only impact the risk for depression by creating susceptibility to specific environmental stressors but also cause individuals to persistently place themselves in highly stressful environments.

The potential clinical relevance of neurogenesis in the adult mammalian brain represents the most recent major breakthrough in depression studies at the cellular neurobiological level. Imaging studies have demonstrated a 10% to 20% decrease in the hippocampal volume of human patients with chronic depression. Cell proliferation studies using 5-bromo-2′-deoxyuridine injection to label dividing cells show that antidepressants also lead to increased cell number in the mammalian hippocampus. This effect is seen with chronic but not acute treatment; the time course of the effect mirrors the known time course of the therapeutic action of antidepressants in humans (Czéh et al., 2001). Although a role for neurogenesis in the pathophysiology of depression appears to be a promising avenue of research, the relevance of animal studies described here remains controversial in the human (Reif et al., 2006).

Analysis at the systems level suggests that anterotemporal paralimbic and orbitofrontal regions are involved in mediating primary and acquired depression. Functional imaging studies of unmedicated patients with familial depression reveal increased CBF and glucose metabolism in the amygdala, orbital cortex, and medial thalamus and decreased CBF and glucose metabolism in the dorsomedial/dorsal anterolateral prefrontal cortex and anterior cingulate cortex (Charney and Manji, 2004). Damage to the prefrontal cortex from stroke or tumor, or to the striatum from degenerative diseases such as PD and HD, is associated with depression (Charney and Manji, 2004; Drevets, 2001). Functional imaging studies of subcortical disorders such as these reveal hypometabolism in paralimbic regions, including the anterotemporal cortex and anterior cingulate, which are correlated with depression seen in these patients (Ketter et al., 1996; Mayberg, 2003). Depression in PD, HD, and epilepsy has been correlated with reduced metabolic activity in the orbitofrontal cortex and caudatenucleus.

Mayberg (2003) proposed that primary depression is due to dysfunction in a network that includes two known pathways: the orbitofrontal–basal ganglia–thalamic circuit and the basotemporal limbic circuit that links the orbitofrontal cortex and the anterior temporal cortex by the uncinate fasciculus. Portions of this model are illustrated in Fig. 9.4. This has been expanded into a unifying depression circuit model that consists of four interconnected functional compartments. Each functional compartment consists of strongly interconnected anatomical structures upon which that compartment is dependent. Functional compartments are as follows: mood regulation (medial frontal, medial orbital-frontal and pregenu anterior cingulate cortex), mood monitoring (ventral striatum-caudate, amygdale, dorsomedial thalamus, midbrain-ventral tegmental area), interoception (subcallosal cingulated, ventral-anterior hippocampus, anterior insula, brain stem, hypothalamus) and exteroception (prefrontal, premotor, parietal, mid-cingulate and posterior cingulate cortices with dorsal-posterior hippocampus) (Mayberg, 2009).

Fig. 9.4 Midline sagittal human brain. Frontal lobe, red; parietal lobe, dark blue; occipital lobe, green; temporal lobe, light blue; limbic cortex, orange. Thick black lines approximate a cortical-basal ganglia-thalamic-cortical loop (circuit) to the orbital frontal cortex.

Functional imaging studies of untreated depression have been extended to evaluate responses to pharmacological, cognitive-behavioral, and surgical treatments of depression. Clinical improvement after treatment with serotonin-specific reuptake inhibitors such as fluoxetine correlates with increased activity on PET in brainstem and dorsal cortical regions including the prefrontal, parietal, anterior, and posterior cingulate areas, and with decreased activity in limbic and striatal regions including the subgenual cingulate, hippocampus, insula, and pallidum (Mathew et al., 2003). These findings are consistent with the prevailing model for involvement of a limbic-cortical-striatal-pallidal-thalamic circuit in major depression. The same group has shown that imaging can be used to identify patterns of metabolic activity predictive of treatment response. Hypometabolism of the rostral anterior cingulate characterized patients who failed to respond to antidepressants, whereas hypermetabolism characterized responders. Dougherty and coworkers (2003) used PET to search for neuroimaging profiles that might predict clinical response to anterior cingulotomy in patients with treatment-refractory depression. Responders displayed elevated preoperative metabolism in the left prefrontal cortex and the left thalamus. A combination of functional imaging and pharmacogenomic technologies might allow subsets of treatment responders to be classified and predicted more precisely than with either technology alone. Goldapple and coinvestigators (2004) used PET to study the clinical response of cognitive-behavioral therapy in patients with unipolar depression and found increases in hippocampus and dorsal cingulate and decreases in dorsal, ventral, and medial frontal cortex. The authors speculate that the same limbic-cortical-striatal-pallidal-thalamic circuit is involved but that differences in the direction of metabolic changes may reflect different underlying mechanisms of action of cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs).

Clinical Symptoms and Signs Suggesting Neurological Disease

Many neurological conditions have associated psychiatric symptoms. Psychiatrists and neurologists need to be intimately acquainted with features of the clinical history and examination that indicate the need for further investigation. Box 9.3 outlines some key features that have historically suggested an underlying neurological condition. Box 9.4 (online only at www.expertconsult.com) reviews some key areas of the review of systems that can be helpful when assessing for neurological and medical causes of psychiatric symptoms. Table 9.3 (online only at www.expertconsult.com) reviews abnormalities in the elemental neurological examination associated with diseases that can exhibit significant neuropsychiatric features.

Table 9.3 Neurological Abnormalities Suggesting Diseases Associated with Psychiatric Symptoms

ALS, Amyotrophic lateral sclerosis; DLB, dementia with lewy bodies; HD, Huntington disease; MS, multiple sclerosis; PSP, progressive supranuclear palsy; WD, Wilson disease.

Psychiatric Manifestations of Neurological Disease

Virtually any process that affects the neuroanatomical circuits described earlier can result in behavioral changes and psychiatric symptoms at some point. Psychiatric symptoms may be striking and precede any neurological manifestation by years. Table 9.4 (online only at www.expertconsult.com) lists conditions that can be associated with psychosis or depression. Box 9.5 summarizes some key points from the preceding discussion. A general overview and discussion of a number of major categories of neurological and systemic conditions with prominent neuropsychiatric features follows. More detailed information regarding the evaluation, natural history, pathology, and specific treatment recommendations for these conditions is beyond the scope of this chapter.

Table 9.4 Selected Neurological and Systemic Causes of Depression and/or Psychosis

Treatment Modalities

Persons with mild to moderate major depression may benefit equally from psychotherapy or medication. Patient preference remains the primary factor in choosing initial therapy. Severely depressed patients benefit more from antidepressant medication, alone or in combination with psychotherapy, than from psychotherapy alone. Three types of psychotherapeutic options have proven to be effective for treatment of depression: CBT, interpersonal therapy (IPT), and problem-solving therapy (PST). The aim of CBT is to modify thoughts and behaviors to yield positive emotions. It may help prevent relapse in patients with a history of recurrent depression. IPT requires the capacity for insight and targets conflicts and role transitions contributing to depression. In PST, patients learn to cope better with specific everyday problems.

Clinicians face a wide array of antidepressant drug options (Table 9.7). The most commonly prescribed drugs are the second-generation antidepressants: SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and bupropion. First-generation antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]) offer similar effectiveness, but with more toxicity. Generally, TCAs are avoided because of considerable dry mouth, constipation, and dizziness. TCAs are relatively contraindicated in patients with coronary artery disease, congestive heart failure, and arrhythmias. They are also potentially fatal in overdose. MAOIs are also used infrequently, even by psychiatrists, because of the many dietary restrictions and the potential for hypertensive crisis. The selegiline patch (20-mg formulation) is a U.S. Food and Drug Administration (FDA)-approved MAOI that does not require dietary tyramine restrictions. Antidepressant selection is based on tolerability, safety, evidence of effectiveness in the patient or a first-degree relative, and cost. The goal of treatment is complete remission of symptoms and return to normal functioning. About 50% of patients achieve full remission with antidepressant therapy, while the other half achieves partial remission or are nonresponders. For the first episode, antidepressant treatment may take 1 to several months until remission is achieved, and medication should be continued for another 4 to 9 months. Some clinicians advocate treatment for at least 1 year to maintain remission for a full annual cycle of holidays and anniversaries. For patients older than 70 years who respond to an SSRI, consider treating for 2 years to prevent recurrence. Increasing the dose of the current medication or changing medications is often necessary. For a partial response, the dose of the initial agent should be maximized as tolerated before switching to another medication or adding a second drug. When a partial response continues, the clinician can refer for psychotherapy, change antidepressants, or augment treatment with bupropion, mirtazapine, or a nontraditional agent. Compared with withdrawing one drug and initiating another, combination therapy offers faster effects and avoidance of withdrawal symptoms when stopping the first agent. Combinations of MAOIs and either SSRIs or TCAs are not recommended because of an increased risk for serotonin syndrome (with confusion, nausea, autonomic instability, and hyperreflexia). Adding adjunctive atypical antipsychotics, psychostimulants, and thyroid hormone remains controversial. Antipsychotics added to SSRIs for treatment-resistant depression show some benefit but also carry significant risks, so their use should be limited to psychiatrists (Shelton and Papakostas, 2008). A Cochrane review of monotherapy treatment with psychostimulants (dexamphetamine, methylphenidate, methyl amphetamine, and pemoline) for moderate to severe depression found short-term improvement in depression symptoms and fatigue (Candy et al., 2008). A second review of 19 controlled trials on adults older than 65 years supported this recommendation for methylphenidate (Hardy, 2009).

Table 9.7 Medication Treatment for Depression

ARA, α₂-Receptor antagonist; ECG, electrocardiogram; MAOI, monoamine oxidase inhibitor; NDRI, norepinephrine and dopamine reuptake inhibitor; OCD, obsessive compulsive disorder; SNRI, serotonin and norepinephrine reuptake inhibitor; SRA/A, serotonin receptor antagonists/agonists; SSRI, selective serotonin reuptake inhibitor.

* Dose range for geriatric patients is in parentheses.

† Wright, S.K., Schroeter, S., 2008. Hyponatremia as a complication of selective serotonin reuptake inhibitors. J Am Acad Nurse Pract 20, 47–51.

‡ Kroenke, K., Krebs, E.E., Bair, M.J., 2009. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry 31, 206–19.

Studies are conflicting about the effectiveness of adding thyroid hormone (triiodothyronine [T₃] and levothyroxine [T₄]) to antidepressants. More research is needed before these therapies can be recommended. Augmentation with other nontraditional agents has also shown mixed results: omega-3 fatty acids added to sertraline in patients with coronary heart disease did not improve depressive outcomes (Carney et al., 2009). For seasonal depression, light therapy, 6000 to 10,000 lux for 30 to 90 minutes each morning may be helpful (Golden et al., 2005). Yoga, exercise (Mead et al., 2009), self-help books, and relaxation therapy (Morgan and Jorm, 2008) may also be useful. Specific types of side effects are more common with particular drugs and should guide choice of medications (see Table 9.7). Sexual side effects of SSRIs include decreased libido or interest (men and women), anorgasmia (women), and delayed ejaculation (men). To address these side effects, consider pretreatment counseling, switching to a drug with a different mechanism of action (e.g., bupropion, mirtazapine), or using sildenafil for SSRI-associated erectile dysfunction if there are no contraindications. Switching to bupropion can reduce undesired weight gain. Agitation or excessive activation may occur with fluoxetine and warrants a switch to a different SSRI.

Treatment for schizophrenia is most successful when antipsychotic medications are combined with psychological and social supports. These supports may include CBT, vocational interventions, and the use of multidisciplinary mental health professional teams who work with the patient and caregivers inside and outside the hospital to insure health and social care (van Os and Kapur, 2009). CBT may improve coping and reduce distress and affective symptoms associated with psychotic symptoms. Despite these interventions, about one-third may remain symptomatic. All antipsychotics share varying degrees of striatal D₂ receptor blockade. The first-generation antipsychotics (e.g., haloperidol, perphenazine, chlorpromazine) possess equivalent efficacy but differ in potency and side effects. All potentially produce extrapyramidal symptoms (EPS), tardive dyskinesia, and hyperprolactinemia. The second-generation antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine), also known as atypical antipsychotics, generally produce fewer EPS, less risk of tardive dyskinesia, and less hyperprolactinemia. Table 9.8 lists selected antipsychotic side effects. Some atypical antipsychotics such as clozapine and olanzapine have been associated with weight gain, impairment of glucose metabolism, and dyslipidemia. Clozapine has greater efficacy than first-generation drugs but requires regular blood test monitoring throughout the course of treatment owing to an increased risk for agranulocytosis (1%-4%). Risperidone is known for its association with hyperprolactinemia. The primary symptom targets for antipsychotics are psychotic symptoms, agitation, and negative symptoms (e.g., apathy, social withdrawal, diminished affect). Response times for psychotic symptoms may range from responding within hours of administration to several weeks of administration. Maximal response may require months. Some patients are nonresponders. Agitation responds well to most antipsychotics, but negative symptoms generally respond only modestly.

Treatment Principles

The unique features of each condition discussed should be carefully taken into account when developing a treatment plan. Transient, progressive, or static impairments in abilities such as driving, medical decision making, and management of finances may be present. Increased vigilance when monitoring patients for these impairments may improve care and allow for earlier interventions to protect the welfare of the patient, their family, and society. Patients with underlying neurological conditions tend to be more susceptible to the adverse reactions of psychotropic medications, particularly to extrapyramidal and cognitive side effects. These adverse reactions tend to be minimized with initiation of medications at low doses and use of gentle titration. When clinically indicated, atypical antipsychotics are often preferred over typical agents because of their fewer adverse side effects, but longitudinal studies are needed to better confirm this impression (Lieberman et al., 2005; Tarsy and Baldessarini, 2006). Further options to consider for treatment of refractory primary depression and other carefully selected psychiatric conditions include ECT, VNS (Elger et al., 2000; Groves and Brown, 2005; Marangell et al., 2002; Rush et al., 2000), transcranial magnetic stimulation (Rosa et al., 2006), deep brain stimulation (Skidmore et al., 2006), or stereotactic ablative surgery (Dougherty et al., 2002, 2003; Montoya et al., 2002b; Price et al., 2001). There is currently little evidence to guide the optimal treatment approach for patients with neurological disease and comorbid psychiatric symptoms.

In conclusion, advances in neuroscience have improved our understanding of the neural substrates of cognition and emotional behavior. The traditional boundaries between neurology and psychiatry have become obsolete. The future of psychiatric and neurological care, training, and research will inevitably require effective collaboration between both disciplines (Cunningham et al., 2006; Price et al., 2000).