Handbook of Consultation-Liaison Psychiatry

6. Basic Foundations of Diagnosis, Psychiatric Diagnosis and Final Common Pathway Syndromes

Hoyle Leigh

CONTENTS

6.1 Diagnosis, Multiaxial Diagnosis, and Levels of Diagnosis

6.1.1 Levels of Diagnosis

6.2 Psychiatric Syndromes

6.2.1 Characteristics of Psychiatric Syndromes: Extremes of Adaptive Normal Traits

6.2.2 Brain Areas and Circuits in Normal Emotions and Cognition

6.2.3 Neurotransmitters

6.2.4 The Brain in Psychiatric Syndromes

6.2.5 Final Common Pathways: Genes, Stress, Brain Function and Psychiatric Syndromes

6.3 Final Common Pathway Model

6.3.1 Psychiatric Syndromes as Final Common Pathway Phenomena

6.3.2 Evaluation of Final Common Pathway Psychiatric Syndromes

6.3.3 Management of Final Common Pathway Syndromes

This chapter discusses the basic theoretical and neuroscience foundations of psychiatric syndromes and the diagnostic process. These foundations help in understanding the application of psychiatric diagnosis in the consultationliaison setting.

6.1 Diagnosis, Multiaxial Diagnosis, and Levels of Diagnosis

The word diagnosis derives from the Greek prefix dia, meaning across, apart, or through, and the Greek word gnosis, meaning knowing. Diagnosis, a thorough (through and through) knowing of the patient's illness, including knowing it apart from other possibilities (differential diagnosis), is the essential first step in all medical intervention including psychiatric consultation.

When a psychiatric consultation is requested from our nonpsychiatric colleagues, one or more medical diagnoses is probably at least suspected or being evaluated. The psychiatric consultant is then expected to consider possible psychiatric diagnoses and to integrate an understanding of the patient from the psychiatric, medical, and psychosocial dimensions in making a recommendation.

The multiaxial diagnostic scheme of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; American Psychiatric Association, 1994) is useful in recognizing the possible coexistence and interaction between medical and psychiatric diagnoses, and the interaction of the personality, stress, and social functioning with the illness.

The multiaxial diagnostic scheme, in brief, is as follows:

Axis I: major psychiatric disorders, such as schizophrenia, major depression, anxiety disorders, including psychiatric syndromes caused by medical diseases, e.g., delirium

Axis II: personality disorders or traits (e.g., borderline personality) or developmental disorders (e.g., mental retardation)

Axis III: medical diseases and conditions, e.g., diabetes mellitus, renal failure, status postappendectomy

Axis IV: psychosocial and environmental stressors and problems, e.g., divorce, trouble at work, lack of health care, unemployment

Axis V. Global Assessment of Function (GAF, a 0 to 100 scale, with 0 meaning not able to assess, 10 meaning very severely impaired, and 100 indicating perfect functioning)

Usually the consultant uses a cutoff of 50 on the GAF to determine the need for psychiatric hospitalization; that is, if a patient scores less than 50, there is a need for a protected setting for the patient, for example, psychiatric hospitalization.

The DSM-IV diagnostic scheme has many problems. As it is based on research diagnostic criteria (Feighner et al., 1972) and is designed to obtain a "pure culture" for biologic research, the diagnoses are categorical and mutually exclusive, even though many psychiatric syndromes represent extremes of gradations of symptoms, many of which overlap and coexist. This overlap is not surprising, as the same susceptibility genes may have different phenotypic expressions depending on early experience and stress (See Final Common Pathways, below). Furthermore, there is a continuum of experiences and moods from normality to repeated distress, not quite reaching the criteria for the disorders of frank major psychiatric syndromes. Especially in consultation-liaison settings, patients often experience anxiety and depression associated with both medical conditions and the stress of hospitalization. The term disorder, adopted by DSM-III/IV, is also problematic as it is a vague and pejorative term not commonly used in medicine. "Syndrome" is a better designation widely used in medicine, which term may be substituted for "disorder".

Axis II does not include personality characteristics, personality assets, and coping styles that might be important especially in consultation-liaison settings.

In my opinion, in a future edition of the DSM there should be an axis that records the genes and changes in brain morphology and function that may underlie or contribute to Axis I diagnosis. Axis IV should also include not just recent stressors but, more importantly, the childhood stressors that may have influenced the brain's susceptibility to later stress, and that may have influenced the person's mood and behavior. There should be an axis that records the patient's psychosocial support. Axis V GAF should consider a longer period than 1 year, perhaps 5 years, to assess the longitudinal change in function. Perhaps there should be a radical reconceptualization of the axes for DSM-V.

I find the following modification of the DSM to be useful in consultationliaison psychiatry:

Axis I: psychiatric syndromes and symptoms, e.g., depressive syndrome, psychosis, depression associated with serious diagnosis, anxiety concerning prognosis

Axis II: personality traits and styles (e.g., impulsive, intellectualizing, brooding) and syndromes and developmental problems, e.g., borderline personality, obsessive traits, mental retardation

Axis III: general medical conditions and neuropsychiatric disease, e.g., diabetes mellitus, tertiary syphilis

Axis IV: early (childhood), recent, and current stressors

Axis V. psychosocial assets such as social support (e.g., supportive spouse), personality assets (e.g., intelligence, coping skills), and GAF both recent (for the last 5 years) and current.

6.1.1 Levels of Diagnosis

Thorough knowledge of a patient's illness involves knowing (1) the patient as a person, who has a personal history that determined his or her way of perceiving the self and the outer world, and habitual ways of coping; (2) the illness, which is a result of the interaction between the patient and the effects of disease, for example, pain, discomfort, anxiety, and its treatment, including drugs, procedures, and laboratory tests; and (3) the patient in interaction with the social and physical environment, including the health care personnel, family, and the hospital setting.

Thus, in addition to the five axes cited, one has to also consider who the patient is, what the support systems are, and the nature of the biologic problems that may affect the patient's physical and psychological condition.

Historically, medical diagnosis evolved from the naming of symptoms (e.g., fever), to a syndromic diagnosis based on a cluster of symptoms and signs that might indicate a common pathology (e.g., grippe: influenza; dropsy: glomerulonephritis and congestive heart failure, a term still in use), to the current etiologic diagnosis, that relies heavily on laboratory findings. Etiologic diagnosis is based on the biologic abnormality that is a necessary condition for the development of the syndrome.

Psychiatric diagnosis, on the other hand, has not yet evolved beyond the syndromic stage. Axis I and II diagnoses, with a few exceptions, are based on clusters of symptoms and signs.

6.2 Psychiatric Syndromes

6.2.1 Characteristics of Psychiatric Syndromes: Extremes of Adaptive Normal Traits

Most major psychiatric illnesses are chronic conditions and tend to run in families. This seems to indicate that heredity plays an important role. Yet most psychiatric syndromes consist of symptoms that represent extremes of normal human experiences, such as anxiety, depression, and euphoria. These emotions clearly have evolutionarily adaptive value. Imagine a person who congenitally lacks anxiety, sadness, or pleasure. Survival itself from early childhood, let alone socialization and procreation (and therefore empathy), would be seriously in doubt for such a person!

Many psychiatric conditions are precipitated or exacerbated by stressful events. Once a psychiatric syndrome develops, it often has a course of its own, and is not easily reversible without psychiatric intervention. Taken together, these characteristics indicate that (1) many of the genes that confer susceptibility for psychiatric syndromes probably also subserve normal emotional and cognitive functions, and (2) psychological stress and early environment are important in the eventual precipitation of the illness.

A genetic model that might explain this is the cliff-edged fitness model (Nesse, 2004), in which fitness increases as a trait (or its alleles) increases, and then at a certain point it crashes. An example might be one's ability to be sensitive to others' feelings in social interactions, until it reaches the point of sensing the least amounts of rejection or hostility, leading to anxiety and depression. Some individuals with a very low anxiety threshold might have the equivalent of a highly sensitive smoke-detector alarm that would be a nuisance in normal neighborhoods but might be lifesaving in a fire-prone environment. Some individuals may have inherited such sensitivity genes, which at one time had a great evolutionary advantage. Another example might be the ability to think about and understand others' needs and motivations, until it reaches the level where every word or act of another person attains great significance and ulterior motives that is, paranoia. There is a continuum of emotional and cognitive experiences from normality to abnormality, with repeated abnormal experiences not quite reaching the diagnostic criteria for major syndromes. The subsyndromal personality traits, such as neuroticism (Eysenck, 1990), may predispose an individual to a major syndrome under stress (see Serotonin Transporter Gene, Anxiety, Depression, and Neuroticism, below).

6.2.2 Brain Areas and Circuits in Normal Emotions and Cognition

There are important brain structures and circuits involved in emotions and cognition, the dysfunctions of which may underlie psychiatric symptoms and syndromes. The Web site http://www.thebrain.mcgill.ca/flash/index_i.html has excellent diagrams to use in following the descriptions below.

6.2.2.1 Mood, Emotions, Pleasure, and Sadness

How do we experience mood and emotions? Activations of certain areas of the brain seem to be associated with the subjective experience of emotions and are responsible for the patterns of behavioral/muscular activations we call emotional expression, and for the autonomic and endocrine arousal that accompany emotions (Figs. 6.1 and 6.2). The emotion of pleasure and reward seems associated with the dopaminergic activation of a circuitous pathway, first involving a descending medial forebrain bundle component and then involving the ascending mesolimbic ventral tegmental pathway (Bozarth, 1987; Wise and Bozarth, 1984), eventually activating the dopaminergic nucleus accumbens. The septum, the amygdala, the ventromedial prefrontal cortex, and certain parts of the thalamus also participate in the circuit. The ventromedial prefrontal cortex, with its extensive connections with the limbic system, may link the conscious to the unconscious and ascribe meaning to perceptions by associating them with a meaningful whole. The ventral tegmental pathway can also be activated by various substances including alcohol, amphetamines, exogenous and endogenous opiates, barbiturates, caffeine, marijuana, and nicotine.

Fig. 6.1 Anatomy of the brain. (From http://www.stanford.edu/group/hopes/basics/ braintut/ab5.html, with permission from The Huntington's Disease Outreach Project for Education at Stanford.)

Fig. 6.2 Limbic system. (From http://www.stanford.edu/group/hopes/basics/braintut/ ab5.htm1, with permission from HOPES.)

All of these pleasure centers are interconnected and innervate the hypothalamus, particularly the lateral and ventromedial nuclei. The hypothalamus then activates the ventral tegmental area, as well as the autonomic and endocrine functions through the pituitary gland.

Aversive stimuli that provoke fight or flight responses activate the brain's punishment circuit [the periventricular system (PVS)] to cope with unpleasant situations. This circuit includes the hypothalamus, the thalamus, and the central gray substance surrounding the aqueduct of Sylvius. Some secondary centers of this circuit are found in the amygdala and the hippocampus. The cholinergic punishment circuit stimulates the secretion of adrenocorticotropic hormone (ACTH) as well as the adrenal medulla and sympathetic outflow; ACTH in turn stimulates the adrenal cortex to release adrenocortical hormones. Stimulation of the punishment circuit can inhibit the pleasure circuit; thus fear and punishment can drive out pleasure.

The behavioral inhibition system (BIS), associated with the septohippocam- pal system, the amygdala, and the basal nuclei, receives inputs from the prefrontal cortex and transmits its outputs via the noradrenergic neurons of the locus ceruleus and the serotonergic fibers of the medial raphe nuclei. Serotonin may also play a major role in this system. The BIS is activated when both fight and flight seem impossible and the only remaining behavioral option is to submit passively.

When a sensory stimulus is perceived by the cortex to indicate a danger, it is routed first to the thalamus. From there, the information is sent out over two parallel pathways: the thalamo-amygdala pathway (the "short route") and the thalamo-cortico-amygdala pathway (the "long route"). The short route quickly activates the central nucleus of the amygdala. Then the information that has been processed by the cortex through the long route reaches the amygdala and modifies its response dependent on the cortical evaluation of the threat. This cortical evaluation involves the following steps: (1) The various modalities of the perceived object are processed by the primary sensory cortex. Then the unimodal associative cortex provides the amygdala with a representation of the object. (2) The polymodal associative cortex conceptualizes the object and transmits the information to the amygdala. (3) This elaborated representation of the object is then compared with the contents of explicit memory available through the hippocampus, which also communicates closely with the amygdala.

The hippocampus is also involved in the encoding of the context associated with a fearful experience. The amygdala conveys the gratifying or aversive nature of the experience through connections to the nucleus accumbens, the ventral striatum, the septum, the hypothalamus, the nuclei of the brainstem, and the orbitofrontal, cingulate, piriform, and other parts of the cortex. The combination of stimuli from the amygdala with working memory in the dorsolateral prefrontal cortex may constitute the experience of emotion. The basal ganglia have close connections with the amygdala and are involved with the voluntary expression of emotions. The amygdala has outputs to the nuclei of the sympathetic nervous system in the brainstem and the hypothalamus, controlling the pituitary gland and the endocrine system.

The anterior cingulate gyrus of the frontal lobe seems to be important in emotions and cognition. The subgenual anterior cingulate, together with the rostral cingulate, is considered to be the emotional sector of the anterior cingulate gyrus and it subserves autonomic arousal, reward mechanisms, and emotions, particularly anxiety and sadness in close coupling with the amygdala (Grady and Keightley, 2002; Pezawas et al., 2005).

The dorsal portion of the anterior cingulate, called the cognitive cingulate, is involved with error monitoring and selecting among competing responses. Orbitofrontal cortex plays an important role in decision making in the context of emotional situations. Ventrolateral prefrontal cortex, together with the subgenual cingulate, plays a role in responding to reward contingencies (Fig. 6.3).

Fig. 6.3 Schematic diagram of the human brain that highlights some of the main brain areas and neurotransmitter pathways implicated in reward processes. ("Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence"Reprinted from, CMAJ 20-Mar-01:164(6), Page(s) 817-821 by permission of the publisher. (02001 Canadian Medical Association.)

6.2.2.2 Memory and Cognition

The dorsolateral prefrontal cortex seems to play an important role in reasoning. It stores the memories needed for doing tasks (working memory). The concept of working memory posits that a limited-capacity system temporarily stores information and thereby supports human thought processes. One prevalent model of working memory consists of three components: a central executive, a verbal storage system ("phonological loop"), and a visual storage system ("visuospatial sketchpad") (Baddeley, 2003). It has been proposed that the phonological loop evolved to facilitate the acquisition of language. Visuospatial working memory predicts success in fields such as architecture and engineering. The phonological loop is associated with the left temporoparietal region and activates the Wernicke's and Broca's areas. The visuospatial working memory is an associated analogous area in the right hemisphere and the visual cortex. The central executive, including the reasoning and decision-making function, is probably associated with the frontal lobes.

Declarative memory, that is, the memory of facts and events, seems to be a function of the hippocampus and its connections with the cortex. The hippocampus seems to connect various memory traces in the sensory and association cortices into discrete "episodes" that also include emotion-associated inputs from the limbic system. The hippocampus seems to enable us to "play a scene back" by reactivating this particular activity pattern in the various regions of the cortex. The hippocampus plays an essential role in the consolidation of short-term memory into long-term memory, which may represent various cortical regions activated during an event becoming so strongly linked with one another that they would no longer need the hippocampus to act as their link. Thus, information that has been encoded in long-term memory no longer requires the intervention of the hippocampus. This is the case in particular for general knowledge (semantic memory), which is associated with the activation of the frontal and temporal cortices. The activity in the temporal lobe may correspond to the activation of the fact in question, while the activity in the frontal cortex may correspond to its reaching consciousness. Spatial memory, unlike semantic or episodic memory, appears to be confined to the right hippocampus. Procedural memory, such as how to walk or ride a bike, seems to be stored in motor areas, cerebellum, amygdala, and the basal ganglia, particularly the striatum (Barnes et al., 2005).

6.2.3 Neurotransmitters

Nerve transmission occurs when neurotransmitters bind to specific receptors in the postsynaptic neuron. In addition to potentially causing an action potential, neurotransmitters play a modulating role in the excitability of the neuron depending on specific receptor activation. Many chemicals serve the role of neurotransmitters, including acetylcholine, biogenic amines (dopamine, norepinephrine, serotonin, and histamine), amino acids [y-aminobutyric acid (GABA), glycine, glutamate, aspartate], and neuropeptides (corticotropinreleasing hormone, corticotropin, ACTH, endorphins, substance P, somatostatin, bradykinin, vasopressin, angiotensin II).

There are two types of neurotransmitter receptors: ligand-gated receptors and G-protein-linked receptors. Stimulation of a ligand-gated receptor enables a channel in the receptor to open and permits the influx of chloride and potassium ions into the cell. The positive or negative charges that enter the cell either excite or inhibit the neuron. Ligands for these receptors include excitatory neurotransmitters, such as glutamate and aspartate. Binding of these ligands to the receptor produces an excitatory postsynaptic potential (EPSP). Binding of inhibitory neurotransmitter ligands, such as GABA and glycine, produces an inhibitory postsynaptic potential (IPSP). These ligand-gated receptors are also known as ionotropic or fast receptors.

G-protein-linked receptors are indirectly linked to ion channels through a second messenger system involving G proteins and adenylate cyclase. These receptors modulate the actions of the excitatory and inhibitory neurotransmitters such as glutamate and glycine. G-protein linked receptors are known as metabotropic or slow receptors and examples include GABA-B, glutamate, dopamine (Di and D2), and the 5-hydroxytryptamine (5-HT) receptors 5-HT1A, 5-HTIB, 5-HT IDI 5-HT 2A' and 5-HT 2C*

Several different neurotransmitters can be released from a single nerve terminal, including neuropeptides and biogenic amines. Neuropeptides can act as cotrans- mitters or primary neurotransmitters. As cotransmitters, they bind to specific preor postsynaptic receptors to alter the responsiveness of the neuronal membrane to the action of other neurotransmitters, such as norepinephrine and serotonin.

Glutamate is a pivotal amino acid in the brain. It is derived from a-ketoglutarate, which is one of the intermediates in the Krebs cycle. Glutamatergic neurons are extensively distributed in the brain, comprising more than 50% of the neurons. Glutamate is an excitatory neurotransmitter. There are four types of glutamate receptors: the NMDA (N-methyl-D-aspartate) receptor, the AMPA ((X-amino- 3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor, the kainate receptor, and the metabotropic receptor. The NMDA receptor is regulated by at least five binding sites, that is, those for (1) glutamate, (2) glycine, (3) magnesium, and (4) zinc, and a site that binds to (5) phencyclidine (PCP). The NMDA receptors have a capacity for long-term potentiation (LTP), an activity-dependent increase in synaptic efficiency that is crucial for learning and memory. The NMDA receptors are most densely concentrated in the cerebral cortex, especially the hippocampus, the frontal lobes, the amygdala, and the basal ganglia.

Excess glutamate has been shown to be neurotoxic, and an inability to remove glutamate by glial cells, thus eventually resulting in a hypofunction of the glutamatergic neurons, may underlie the cognitive deficits in schizophrenia as well as in certain dementias.

Nitric oxide may be synthesized and released when the NMDA receptor is stimulated by glutamate, enhancing neurotransmitter release from adjacent synapses and playing a role in LTP. Granule cells of the dentate gyrus of the hippocampus are rich in nitric oxide synthetase.

y-Aminobutyric acid is derived from glutamate and is distributed extensively throughout the brain, playing an inhibitory role. Following its release, GABA can be taken up by the neurons or by astrocytes. There are two basic GABA receptors, GABA-A and GABA-B. Stimulation of the GABA-A receptor increases the permeability to chloride ion, resulting in a hyperpolarization of the neuron or inhibition. The GABA-A receptor has three basic binding sites: for GABA, for benzodiazepine, and for barbiturates. The GABA-B receptor is a G-proteinrelated receptor that increases the efflux of K+ from the cell, causing hyperpolarization. The principal effect of GABA-B agonism is muscle relaxation.

Dopaminergic neurons are widely distributed throughout the brain in three pathways: the nigrostriatal, the mesocorticolimbic, and the tuberohypophysial. There are two primary dopamine receptor-types, Di and D2, both of which act through G proteins. D2 receptors often function as autoreceptors, providing negative feedback.

The mesolimbic and mesocortical dopaminergic systems play an important role in motivation, by attaching cognition of incentive to stimuli. Cocaine increases dopaminergic activity in the mesolimbic areas by inhibiting dopamine reuptake in the ventral tegmental area and the nucleus accumbens. Amphetamine seems more generalized in its action, not only by inhibiting reuptake but also by releasing dopamine from most brain regions. Both cocaine and amphetamine produce feelings of psychological energy and arousal, and cause diminished appetite and sleep. Both cocaine and amphetamine can cause visual and tactile hallucinations and paranoia.

Perception of time intervals may be mediated by dopaminergic spiny neurons located in the striatum of the basal ganglia. Marijuana slows subjective time by lowering the amount of dopamine available, whereas cocaine and methamphetamine accelerates the sense of time by increasing dopamine availability.

Dopaminergic neurons are important in pleasure and reward systems as well as in regulation of movement. They are also important in sustaining attention and concentration.

Overstimulation of D2 receptors in the mesolimbic and mesocortical systems may result in psychotic symptoms, as D2 agonists such as amphetamines can cause them and antagonists like haloperidol can reverse them. An overstimulation of striatal D2 receptors and an understimulation of cortical Di receptors have been postulated for schizophrenia.

There is a significant relationship between dopamine and GABA neurons. In general, GABA acts to reduce the firing of the dopaminergic neurons in the tegmentum and substantia nigra. It forms the basis for benzodiazepine augmentation in the treatment of psychosis. In addition, benzodiazepines may be helpful in cases where there is an overactivity of dopamine in the motor striatum such as Huntington's chorea or tardive dyskinesia. The feedback inhibition from the GABA neurons of the globus pallidus and putamen to the dopaminergic neurons of the substantia nigra is an important modulating force on the activity of the dopamine neurons. For further information, go to http://www. unifr.ch/biochem/DREYER/Neurotransmitters/gaba.htm

The natural brain amine phenylethylamine (PEA), which is also found in chocolate, has been associated with sexual attraction and emotional infatuation. Phenylethylamine concentrations are high in the nucleus accumbens and the frontal and cingulate cortices. Levels spike during orgasm and ovulation. Phenylethylamine is very similar to amphetamine in chemical structure and likewise may act by causing dopamine release, but endorphin release may also be a significant effect.

Histamine is synthesized in the tuberomamillary nucleus of the posterior hypothalamus. These neurons project diffusely to most cerebral areas including the suprachiasmatic nucleus (SCN) and have been implicated in regulating circadian rhythms, ACTH secretion, cardiovascular control, thermoregulation, food intake, and memory formation. Outside of the central nervous system (CNS), histamine is stored in mast cells, whose release causes the allergic reaction. There are three types of histamine receptors: H, receptors, which are widely distributed in the body; H2 receptors, which are distributed in the stomach and the heart; and H3 CNS autoreceptors. There is close interaction between histamine and serotonin, as both are concerned with circadian rhythms and feeding behavior, and in the SCN there is a stimulatory effect of endogenous serotonin on histamine release.

Serotonin is synthesized from L-tryptophan. As there is no rate-limiting enzyme for the synthesis of serotonin in the brain, all L-tryptophan that crosses the blood-brain barrier becomes serotonin. Meals high in branch-chained amino acids and L-tlyptophan or in carbohydrates increase insulin secretion, which facilitates the transport of the branch-chained amino acids into muscle cells, thereby reducing the competition for L-tryptophan for the large neutral amino acid transporter that will transport it across the blood brain barrier. This increase in serotonin often results in drowsiness. The pineal body has the richest concentration of serotonin in the brain, but the pineal serotonin is used for synthesis of melatonin rather than as a neurotransmitter. Serotonin neurotransmitter neurons are located in the raphe nuclei. The caudal nucleus projects largely to the medulla and spinal cord for the regulation of pain perception. The rostral nucleus projects extensively to the limbic system and the cerebral cortex. In the limbic system, the serotonergic receptors are colocalized with norepinephrine receptors, and serotonin and norepinephrine may work in conjunction in the regulation of arousal. At least 15 subtypes of serotonin receptors have been identified.

The SCN of the hypothalamus regulates the mammalian circadian clock. It is richly innervated by serotonergic input from the dorsal raphe nucleus. When light is present, the release of melatonin by the SCN is inhibited. Serotonin also seems to inhibit the responsiveness of the SCN to light.

Serotonin plays an important role in sleep, satiety, and mood. Serotonergic hypofunction in certain areas may underlie depression, aggression, and impulsive behavior.

About 95% of serotonin in the body is outside of the CNS, mainly in the intestines. There are seven families of serotonin receptors, among which 5-HT, and 5-HT2 receptors are mostly in the brain, and 5-HT3 and 5-HT4 receptors are mostly in the gut.

When stretch receptors on the gut wall are stimulated, serotonin, which enhances peristalsis, is released. Vagus nerve stimulates serotonin release in the gut. Current antidepressants that block reuptake of serotonin at synapses often have gastrointestinal side effects.

Serotonin syndrome is a potentially life-threatening adverse reaction to drugs that increase serotonin levels in CNS and the body. Signs of excess serotonin range from tremor and diarrhea in mild cases to akathisia, clonus, delirium, neuromuscular rigidity, and hyperthermia in life-threatening cases. Patients usually manifest mydriasis, hyperactive bowel sounds, and diaphoresis, and show flushing or normal skin color. Creatine phosphokinase (CPK) is usually normal. Serotonin syndrome usually develops rapidly following the ingestion of drug, often in an overdose or drug interaction (e.g., a serotonin reuptake blocker with a monoamine oxidase inhibitor). Management of the syndrome involves the removal of the precipitating drugs, supportive care, control of agitation, prescribing serotonin antagonists (e.g., cyproheptadine), the control of autonomic instability, and the control of hyperthermia. Benzodiazepines are helpful for muscular rigidity and agitation. Olanzapine and chlorpromazine parenterally may also be helpful (Boyer and Shannon, 2005; also go to http://www.benbest. com/science/anatmind/anatmdl0.html#serotonin).

Norepinephrine (noradrenaline)-containing neurons arise mainly from the locus ceruleus in the pons. They project extensively to the cortex, hippocampus, thalamus, and midbrain. Norepinephrine tends to increase the level of excitatory activity within the brain, and seems to be particularly involved in attention, arousal, and anxiety. Norepinephrine is the neurotransmitter of the sympathetic nervous system, and its activation, as in anxiety, has major effects on heart rate and blood pressure. There are benzodiazepine receptors in the locus ceruleus, as well as opiate receptors and az autoreceptors, that all reduce its firing. The beta-blocker propranolol also has been used to treat anxiety. By blocking the adrenergic inputs to the amygdala, beta-blockers may inhibit the formation of traumatic memories. Cortisol stimulation of the locus ceruleus due to chronic stress exacerbates norepinephrine stimulation of the amygdala.

Acetylcholine is abundant in the interpeduncular nucleus located near the substantia nigra, and all the interneurons in the striatum and the nucleus accumbens are cholinergic. The septum provides cholinergic fibers to the septalhippocampal tract. The primary cholinergic input to the cerebral cortex comes from the basal nucleus of Meynert, which also innervates the basolateral amygdala, the basal ganglia, and the reticular nucleus of the thalamus. Cholinergic transmission is important in cognition and sleep, and is the main neurotransmitter in the parasympathetic nervous system as well as in muscles. There are two types of cholinergic receptors: fast-acting nicotinic receptors and slowacting muscarinic receptors. The presynaptic parasympathetic fibers and fibers innervating the voluntary muscular system are nicotinic, which are antagonized by curare. Atropine, which blocks the muscarinic receptors, can cause memory loss, and there seems to be a deficiency of muscarinic cholinergic transmission in patients with Alzheimer's disease. Postganglionic parasympathetic fibers are also muscarinic.

Oxytocin is a nonapeptide released from the paraventricular nucleus of the hypothalamus through the posterior pituitary. It is a central mediator of prosocial behavior. Oxytocin is also released during stress and is an important modulator of anxiety and fear response (McCarthy et al., 1996).

6.2.4 The Brain in Psychiatric Syndromes

6.2.4.1 Prefrontal Cortex

In the prefrontal cortex, the ventromedial cortex seems affected by both depression and mania. It is located on either side of the center line separating the two hemispheres and is closely involved with the pleasure circuit. It also seems to be involved in switching from one kind of affect to another. The ventromedial cortex has extensive connections with the limbic system (Fellows and Farah, 2003). The volume of the ventromedial cortex is decreased in chronic depressives, mostly owing to a decrease in the number of glial cells.

There seems to be a hyperactivity of the rostral and subgenual cingulate in depression, and hyperactivity of the rostral cingulate may be a predictor of the response to antidepressant therapy (Grady and Keightley, 2002; Pizzagalli et al., 2001).

The dorsolateral prefrontal cortex (DLPFC) is involved in executive functions and working memory, which are particularly disturbed in schizophrenia. In schizophrenia, there is cortical thinning within the cingulate, occipital, and fron- topolar cortices, and a reduction in overall brain volume. Functional imaging studies show a reduction in neuronal density and activity in the prefrontal cortex and hippocampus in schizophrenia (Jann, 2004).

6.2.4.2 Locus Ceruleus

The locus ceruleus, which supplies a majority of noradrenergic neurons in the brain, plays an important role in anxiety and in activating physiologic and behavioral arousal.

6.2.4.3 Basal Ganglia

The basal ganglia, including the caudate and substantia nigra and thalamus, show hyperactivity in obsessive-compulsive disorder (OCD), and dopaminergic cortico- striato-thalamic circuit dysfunction has been postulated for this disorder (Graybiel et al., 2000). Provocation of OCD symptoms is associated with an increase in cerebral blood flow in the orbitofrontal cortex, anterior cingulate cortex, striatum, and thalamus (McGuire et al. 1994; Rauch et al. 1994). Hypofunction of serotonergic neurons arising from the rostral raphe nucleus may result in a lack of inhibitory effect on the putative OCD pathway. Successful treatment with pharmacotherapy or cognitive-behavioral therapy have resulted in reversal of some of the brain activation (Carey et al., 2004; Schwartz et al., 1996).

6.2.4.4 The Limbic System and the Amygdala

Intimately involved in all things emotional, the limbic system, and particularly the amygdala, is dysregulated in psychiatric syndromes. Functional imaging studies show an increase in activation of the limbic structures, including the amygdala, hippocampus, and adjacent temporal cortex, in anxiety states including phobia. As described below, a dysfunction of the circuit that connects the amygdala to the anterior cingulate gyrus may underlie anxiety and depressive syndromes.

6.2.5 Final Common Pathways: Genes, Stress, Brain Function, and Psychiatric Syndromes

The net result of activations of various parts of the brain manifests itself in the efferent pathways of behavior (motoric), in the hypothalamic-pituitary-adrenal axis (autonomic and endocrine), and in intracranial subjective cognitive and emotional experiences. When these manifestations are dysfunctional or disordered, a psychiatric syndrome results.

We are at the threshold of understanding the genetic mechanisms of emotions and psychosis, and of understanding how some of the genes might be turned on or off by environmental and developmental factors and how brain structures and stress may interact, resulting in normal emotions/behavior or a psychiatric syndrome.

6.2.5.1 Serotonin Transporter Gene, Depression, Anxiety, and Nenroticism

Mutations in the serotonin transporter promoter gene have been implicated in OCD, social anxiety, and severe depression (Murphy et al., 2004b). A variable number of tandem repeats in the serotonin (5-HT) transporter gene linked polymorphic region (5-HTTLPR), located at the SLC6A4 locus on chromosome 17 (17g11.1-17g12) influences the transcriptional activity and subsequent availability of serotonin [see National Center for Biotechnology Information (NCBI) map Web site for 5HTTLPR gene at http://www.ncbi.nlm.nih.gov/mapview/ maps. cgi?taxid=9606&chr= 17&MAPS=morbid,genec,ugHs,genes,pheno%5B2 4579425.12:27953447.37%5D-r&query=uid(7812322,5968)&QSTR=SLC6A4.] The 5-HTTLPR short allele "s" has reduced transcriptional efficiency compared with the long allele, and individuals carrying the "s" allele tend to show increased anxiety responses and seem to show an increased risk of depression (Lotrich and Pollock, 2004). The short-allele carriers show reduced gray matter in limbic regions critical for processing of negative emotion, particularly the perigenual cingulate and amygdala.

Functional magnetic resonance imaging (MRI) studies of fearful stimuli show a tightly coupled feedback circuit between the amygdala and the cingulate, implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit, and the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety (Pezawas et al., 2005). The short-allele carriers have also been reported to have an increased risk for irritable bowel syndrome (Yeo et al., 2004). Furthermore, stress in adulthood and maltreatment in childhood interacted with the 5HTTLPR status in that individuals with two copies of the short allele who had these stressors had more depressive symptoms and suicidal ideation than did heterozygous individuals, and those with only the long alleles had the less depression (Caspi et al., 2003). The short-allele carriers have been shown to have more neuroticism scores on the Eysenck Personality Inventory, and those with both short allele and high neuroticism are at higher risk of developing lifetime depression (Munafo et al., 2005).

5-HTTLPR short-allele carriers with neuroticism have been found to be more likely to smoke, especially to reduce negative mood and to feel stimulated, and have the most difficulty in quitting smoking (Hu et al., 2000; Lerman et al., 2000).

Depressed individuals with the short allele may respond better to antidepressants that are both serotonergic and noradrenergic (e.g., mirtazapine) rather than serotonin-specific reuptake blockers. On the other hand, individuals with the long allele may have more side effects with exactly those drugs that are more effective for those with the short allele (Murphy et al., 2004a). This is an elegant example of genetic polymorphism and resulting brain structural variations interacting with stress and producing susceptibility to anxiety and depression, and influencing the treatment choice (Fig. 6.4).

Fig. 6.4 Serotonin transporter promoter polymorphism (5-HTTLPR s/s) and emotional hypersensitivity to negative stimuli. Differences in processing of emotional stimuli between s allele carriers (darker arrows) and homozygous l allele carriers (light arrows). Negative emotional stimuli are evaluated by the amygdala (arrow from eyes) after preliminary analysis in the ventral visual pathway (not shown). Carriers of the s allele have markedly reduced positive functional coupling between the rostral anterior cingulate (rACC; lower oval) and the amygdala, which results in a net decrease in inhibitory feedback from the caudal anterior cingulate (cACC; upper oval), via connections between rACC and cACC (short upward arrows). Brain volume was also substantially reduced in s allele carriers in the rACC and, to a lesser extent, the cACC and amygdala. The consequence of these genotype-based alterations is an emotional hyperresponsivity to negative affective stimuli in s allele carriers (large dark cloud) compared with individuals lacking this allele (small lighter cloud), which may be related to an increased risk of developing depression. As found in a previous study, functional coupling between the vmPFC (light circle) and the amygdala was also increased in s allele carriers. (From Hamann, 2005. Reprinted by permission from Macmillan Publishers, Ltd: Nat Neurosci, copyright 2005.)

6.2.5.2 Monoamine Oxidase Gene

Similar interactions have also been reported with functional polymorphism in the gene encoding the monoamine oxidase A (MAOA), located on the X chromosome Xp11.4-11.3 (see NCBI map Web site for MAOA gene at http://www. ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&chr=X&MAPS=genec, ugHs, genes-r&cmd=focus&fill=40&query=uid(3805)&QSTR=monoamine%20 oxidase). It encodes the MAOA enzyme, which metabolizes neurotransmitters such as norepinephrine (NE), serotonin (5-HT), and dopamine (DA), and renders them inactive. Genetic deficiencies in MAOA activity have been associated with aggression in mice and humans (Rowe, 2001). Maltreated males with the low-MAOA activity genotype were more likely than non-maltreated males with this genotype to develop conduct disorder in adolescence and be convicted of violent crimes in adulthood. In contrast, among males with high MAOA activity, maltreatment did not confer significant risk for either conduct disorder or violent conviction (Caspi et al., 2002).

6.2.5.3 Stress and the Aging Process

Stress affects the aging process directly at the cellular level. Perceived stress and chronicity of stress was significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length known determinants of cell senescence and longevity. Telomeres are DNA-protein complexes that cap chromosomal ends, promoting chromosomal stability. When cells divide, the telomere is not completely replicated, leading to telomere shortening with every replication. In one study, women who had highest levels of perceived stress had telomeres that were, on the average, at least a decade older than women with lowest stress levels (Epel et al., 2004).

6.3 Final Common Pathway Model

6.3.1 Psychiatric Syndromes as Final Common Pathway Phenomena

The final common pathway model of psychiatric syndromes may be described as follows: Genes adapted to serve various normal emotional and cognitive functions have natural variations. Some such genes may confer susceptibility to exaggerated reactions to stress, particularly if coupled with childhood stress. The final common pathway leading to pathology would be a functional cliff-edge change in the functional status of brain regions, such as a decoupled feedback loop.

Final common pathway syndromes are phenomenologic diagnoses with potentially multiple etiologies and contributing factors. Once having made the syndromic or phenomenologic diagnosis, it is important to elucidate the potential etiologic and contributing factors as well as the protective and mitigating factors such as social support and coping skills (Figs. 6.5 and 6.6).

6.3.2 Evaluation of Final Common Pathway Psychiatric Syndromes

As most psychiatric syndromes represent a final common pathway change in the specific areas of brain function, it is crucial to evaluate the various paths that may contribute to the syndrome. In general, the following factors should be considered in a systematic evaluation:

Fig. 6.5 Final common pathway model.

1. Susceptibility genes: As a direct assessment of the susceptibility genes is not yet a practical diagnostic tool in psychiatry, taking a careful family history for psychiatric syndromes/symptoms is helpful. If family members responded to a particular medication, that medication should be seriously considered for the patient.

2. Onset: A careful inquiry concerning onset of the psychiatric symptom helps differentiate between an ongoing chronic psychiatric illness (that might also be exacerbated by the stress of a nonpsychiatric illness or hospitalization) and a psychiatric condition directly secondary to a medical illness, medications, or medical disability.

3. Secondary psychiatric syndromes: This step entails recognition of, or ruling out, a medical illness, a prescribed medication, or a recreational drug contributing significantly to the psychiatric symptoms. Many medical illnesses and conditions cause psychiatric syndromes directly, particularly endocrine/metabolic disorders, infections, neoplasms, CNS diseases, and cardiovascular diseases. The mechanism by which nonpsychiatric illnesses cause psychiatric syndromes varies, from direct endocrine effect, paraneoplastic syndrome, to direct tissue destruction in a CNS disease. Prescribed medications and recreational drugs often cause psychiatric complications that range from delirium, to anxiety, to depression, to psychosis (Table 6.1).

Fig. 6.6 A model of the final common pathway syndrome. An imbalance between salutary and pathogenic factors results in a cliff-edge cascade of brain dysfunction.

4. Primary psychiatric syndrome: Consideration of the above three parameters will enable the consultant to decide whether the psychiatric syndrome is predominantly secondary or primary. Primary psychiatric syndromes are the final common pathway syndromes resulting from interactions of genetics, early experience, environment, and stress rather than due to an identifiable nonpsychiatric illness, a prescribed medication, or a recreational drug. An example of secondary psychiatric syndrome would be major depression secondary to pancreatic cancer. The consultant may also diagnose a combination of both primary and secondary psychiatric syndrome, for example, schizophrenia, with visual hallucinations and confusion secondary to delirium caused by morphine.

In making a primary psychiatric disorder diagnosis, the clinician should refer to the DSM, published by the American Psychiatric Press, for diagnostic criteria and coding. Alternatively, the International Classification of Diseases (ICD-10), published by the World Health Organization (http://www3.who.int/icd/vollhtm2003/fr-icd.htm), may be used.

5. Role of stress: Stress has impact on the pathogenesis of psychiatric final common pathway syndromes in several ways by increasing the individual's susceptibility, by precipitating the onset of the syndrome, and by precipitating a recurrence or contributing to exacerbation of the syndromes.

6.3.3 Management of Final Common Pathway Syndromes: How to Change the Brain with Psychotherapy and Pharmacotherapy

Multiple interacting paths, some sequential, others parallel, may lead to a final common pathway syndrome. The treatment and management of such a syndrome may also follow multiple interacting sequential or parallel paths. For example, the depressive syndrome may be treated with a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine; a serotonin and norepinephrine reuptake inhibitor (SNRI), such as venlafaxine; or electroconvulsive therapy, in conjunction with either cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT). All of these treatments may be done after an environmental change (admission to a psychiatric unit). The susceptibility for depression in some individuals with 5-HTLPR short allele may be attenuated if maltreatment in childhood was prevented, and eventually, by genetic engineering to modify the pathogenic aspects of the genome.

Judicious use of treatment modalities in biologic, psychological, and social/environmental dimensions is indicated in managing final common pathway syndromes. Protecting an acutely suicidal patient through hospitalization may be the first priority, followed by psychoeducation (both of patient and family) and antidepressant drug therapy as well as psychotherapy. Brain function imaging studies show that both drug therapy and psychotherapy affect the functional status of the brain when successful.

In depression, with successful treatment with CBT or IPT, patients exhibited decreased activity in dorsal frontal regions and increased activity in ventral frontal and subcortical regions (notably including limbic and paralimbic structures). Of note is that the brain changes seen with psychotherapy of depression, unlike those in OCD or phobias, are different from those seen with successful treatment with medications, which results in an increase in prefrontal cortex metabolism and a decrease in the activity in the posterior cingulate and in the subgenual cingulate, and may represent different mechanisms of recovery from depression (Goldapple et al., 2004; Roffman et al., 2005).

In OCD, behavioral therapy reduces the metabolism in the caudate nucleus. Both fluoxetine and psychotherapy seem to uncouple dysfunctional cortico- striato-thalamic circuitry.

In phobias, patients have significant activation in the parahippocampal gyrus and right dorsolateral prefrontal cortex as compared to normals. With successful CBT utilizing exposure therapy, patients demonstrated significantly less activation in both the parahippocampal gyrus and right dorsolateral prefrontal cortex (DLPFC), and increased activation in the right ventral prefrontal cortex (PFC) (Paquette et al., 2003). The abatement of the parahippocampal gyrus response may be due to a dampening of contextual memory believed to be mediated by this structure. A shift of activity to the ventral PFC could prompt downregulation of limbic activity, dampening the fear reaction.

In social phobia, CBT that targeted the anxiety associated with public speaking demonstrated a significant reduction of activity in the limbic system including the amygdala. Psychotherapy and pharmacotherapy seem to have differential effects in phobia. Citalopram, an SSRI, reduced the activity of ventral prefrontal cortex in phobics, while CBT caused no change. Patients receiving CBT showed decreased CBF in the periaqueductal gray area, which has been associated with defense behaviors. Citalopram reduced the blood flow to the thalamus, potentially reflecting reductions in sensory input to the amygdala (Charney and Deutch, 1996).

In schizophrenia, the functional hypofrontality has been partially reduced with second-generation antipsychotic drugs (see Chapter 10), and the limbic overactivation of D2 neurons are reduced with antipsychotics in general.

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