The Functional Anatomy, Neurochemistry, and Pharmacology of Anxiety

Philip T. Ninan The Functional Anatomy, Neurochemistry, and Pharmacology of Anxiety Philip T. Ninan, M.D. © Copyright 2000 Physicians Postgraduate Press, Inc. The functional anatomy of anxiety involves amygdala-based neurocircuits with critical reciprocal connections to the medial prefrontal cortex. Traumatic experiences leave emotional imprints involving the amygdala, with facilitated fear-conditioned associations involving declarative memory traces. Avoidance conditioning is an additional component. An understanding of the functional anatomy of anxiety allows for a new perspective on the various anxiety disorders. The neurotransmitters involved in these circuits are reviewed for their relevance to the pharmacologic choices in the treatment of anxiety. Potent serotonin reuptake inhibitors appear to have superior efficacy in many of the anxiety disorders, with indications that norepinephrine reuptake inhibitors have an advantage in severe forms of major depression. Medications with dual effects—blocking reuptake of both serotonin and norepinephrine (e.g., clomipramine and venlafaxine XR)—have superior benefits in achieving remission in major depression and GAD. These medications may also offer a faster onset of action and theoreti- cally superior benefitsOne in patients personal with comorbidcopy may anxiety be disorder printed and major depression. (J Clin Psychiatry 1999;60[suppl 22]:12–17) If the human brain were so simple that we could understand somatization all describe overlapping or equivalent expe- it, we would be so simple that we couldn’t. riences for individuals. If symptomatic overlap occurs in different diagnostic —Emerson Pugh, 1997 conditions, it is not surprising that syndromal overlap also occurs, given that our syndromal labels are derived from urrent psychiatric nosology, codified in the DSM-IV, symptomatic criteria. The National Comorbidity Survey C defines diagnostic categories using signs and symp- reported that 58% of patients with major depression also toms. Thus, generalized anxiety disorder (GAD) has the suffered from an anxiety disorder.2 Additionally, major de- key component of worry, with associated symptoms of pression is a common lifetime comorbidity in GAD, panic restlessness, fatigue, impaired concentration, irritability, disorder, social phobia, obsessive-compulsive disorder muscle tension, and sleep disturbance. Diagnostic catego- (OCD), and posttraumatic stress disorder (PTSD). Thus, ries that share core symptoms are grouped as disorders. comorbidity of anxiety and mood disorders is the rule The core symptom in the anxiety disorders is the excessive rather than the exception. In 68% of such individuals with experience of anxiety, which can manifest in different both an anxiety disorder and major depression, the anxiety forms such as panic, avoidance, intrusive experiences, or disorder preceded the major depression. There was an av- patterns of cognition. Anxiety, however, is not unique to erage of 11 years between the development of the anxiety anxiety disorders. The majority of patients with major de- disorder and major depression in these individuals.2 For pression experience pathologic anxiety as a symptom.1 clinicians, the implication is that successful treatment of Confusion arises as terms like anxiety can encompass dif- such individuals would require adequate management of ferent experiences and observed behaviors. Thus, nervous- both the anxiety disorder as well as the major depression. ness, tension, irritability, agitation, restlessness, worry, and Only then will the individual have a chance of achieving wellness. THE FUNCTIONAL ANATOMY OF ANXIETY From the Emory University School of Medicine, Atlanta, Ga. Fear is a normal response to threat, while anxiety can Presented at the Depression/Anxiety Working Group be defined as unwarranted or inappropriate fear.3 The pro- Conference, a scientific experts’ meeting, held January 30–31, tective response to aversive threat is an evolutionarily 1999, in Dallas, Tex. This conference was supported by an unrestricted educational grant from Wyeth-Ayerst maintained, unconditioned response “hard-wired” in the Laboratories. brain. The fear/anxiety response does not have to be Reprint requests to: Philip T. Ninan, M.D., Emory University School of Medicine, 1841 Clifton Rd., Room 401, learned and includes defensive behaviors, autonomic Atlanta, GA 30329. arousal, hypoalgesia, potentiation of somatic reflexes, and 12 J Clin Psychiatry 1999;60 (suppl 22) Neurobiology of Anxiety activation of the “stress” axis through the hypothalamic- Table 1. Mediation of the Fear/Anxiety Response Through the pituitary-adrenal (HPA) axis.3 An amygdala-based neuro- CnA Output Pathwaysa circuit has been proposed to mediate the fear and anxiety CnA Output Pathway Fear/Anxiety Response response.4 The amygdala is central to registering the emo- Lateral hypothalamus ➞ Sympathetic activation tional significance of stimuli and the development of emo- DMN of vagus/nucleus ambiguous ➞ Parasympathetic activation Parabrachial nucleus ➞ Dyspnea/hyperventilation tional memories. The output pathways of the central VTA/locus ceruleus/dorsolateral ➞ Behavioral and EEG arousal, nucleus of the amygdala (CnA) can explain various symp- tegmental nucleus increased vigilance toms experienced in anxiety states (Table 1).4 Nucleus reticularis pontis caudalis ➞ Increased startle Midbrain central gray ➞ Freezing, fear of dying Optimal© Copyrightactivity in the anxiety 2000 circuits Physicians is associated Trigeminal/facialPostgraduate motor nerve Press,➞ Facial Inc. expression of fear with a normal readiness to respond to situations and a flex- Paraventricular nucleus ➞ HPA axis activation ible, motivated state of being. Exaggerated challenges in- aAdapted with permission from Davis.4 Abbreviations: CnA = central nucleus of the amygdala, DMN = dorsomedial nucleus, duce anxiety, and resources are marshaled to respond. HPA = hypothalamic-pituitary-adrenal, VTA = ventral tegmental area. Life-threatening challenges result in the permanent imprinting of the experience in the emotional circuits through the amygdala, encompassing the full emotional barrassment; in PTSD, the emotional memory of the memory of the experience. Associated cues are stored trauma; in OCD, the intrusive obsessional ideas; and in through the declarative memory circuits involving the hip- GAD, anxiety, not conditioned to specific triggers (i.e., pocampus. This allows for associated cues to trigger the free-floating). emotional memory of the trauma, bringing it to conscious Normality, derived from this model, can be defined as awareness (conditioned fear). AvoidanceOne personal conditioning copy al- may thebe capacityprinted to vary, choose, and control the emotional, lows for the individual to avoid associated sensory, cogni- cognitive, behavioral, and interpersonal responses to a tive, or other stimuli that potentially trigger the emotional given situation. Pathology is the limitation of those imprint of the trauma. choices to a specific pathway. In anxiety disorders, that The medial prefrontal cortex is reciprocally connected pathway is through amygdala-mediated circuits, resulting with the amygdala, allowing for self-imposed regulation in the experience of anxiety and characteristic patterns of of affect and the modulation of autonomic and neuroendo- cognition. The anxiety circuits can be seen as having “hi- crine function.5 This allows for the “cognitive” control of jacked” the larger repertoire of choices the brain is other- the “anxiety” response. New memories with more benign wise capable of. associations can result in the extinction of the emotionally traumatic memory. However, the original imprint still ex- THE NEUROCHEMISTRY OF ANXIETY ists, as it can be reawakened with new experiences of simi- lar threat or specific association cues. Several neurotransmitters mediate the different compo- In times of increased challenge, the control shifts from nents of anxiety, including excitatory amino acids such as the prefrontal “executive” centers to primordially lower glutamate, inhibitory amino acids such as γ-aminobutyric centers such as the amygdala.6 Behaviors are then guided acid (GABA), and monoaminergic neurotransmitters such by patterns conditioned from earlier anxious/traumatic ex- as catecholamines and indoleamines. Different aspects of periences or species-typical–programmed ones. The pre- the anxiety response are mediated by various neurotrans- frontal cortical functions such as working memory are mitters in anatomically distinct areas. Thus, imprinting of taken “off-line” under these circumstances. emotionally traumatic memories is mediated, in part, by The functional anatomy of the anxiety response with its norepinephrine action through the β-adrenergic receptor various elements allows a different conceptual perspective in the amygdala. Administration of a β-blocker prior to a on the nature of anxiety disorders. The emotional and so- trauma may prevent the emotional imprinting of the traumatic experience of anxiety is mediated by output from matic memory.7 The development of conditioned fear is the CnA. Anxiety is associated with a loss of otherwise mediated by dopamine-1 (D1) receptors in the amygdala, broader cognitive capabilities to drive behavior, as emo- leading to facilitation of the declarative memory associa- tionally driven circuits result in characteristic limited pat- tions through the hippocampus.8 LeDoux3 suggests that terns of thinking and behavior. The potential cues for trig-

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