Disorders of Anxiety and Impulsivity and the Drugs Used to Treat These Disorders

Neurobiology of Anxiety

• Anxiety is a disturbing feeling of concern accompanied by bodily changes including activation of the “fight-or-flight” response that prepares an animal to cope with impending danger.
• Fear and anxiety differ in duration, psychological consequences, and neurobiology.
• Many brain regions (including the insula, cingulate cortex, hypothalamus, and hippocampus) are involved in emotion processing, but the amygdala plays a central role.
• The central nucleus of the amygdala and the BNST project widely and orchestrate the components of the emotional response. The central nucleus organizes the fear response when threatening stimuli appear suddenly and end abruptly. The BNST orchestrates components of emotion to produce sustained preparedness for unclear danger, a state resembling anxiety.
• The amygdala forms emotional memories and enhances semantic memory consolidation by the hippocampus.
• Regions of the prefrontal and cingulate cortices exert inhibitory control over the amygdala and mediate fear extinction.
• Anxiety disorders may arise from an imbalance between emotion generating brain regions and higher cortical control.
• CRF regulates stress hormone secretion and activates neuronal circuits of emotion that produce anxious behaviors in animal models.
• Noradrenergic neurons in the LC are activated by threatening stimuli and produce hypervigilance and fearfulness. Stress-induced CRF release by the amygdala causes LC neurons to fire at a high tonic rate. Other LC cells respond to non-noxious stimuli with phasic bursts of activity.
• NE, aided by adrenal cortisol, mediates the formation and reconsolidation of traumatic memories. Elevated adrenergic function is found in some anxiety disorders. Several therapeutic drugs modulate LC firing by several different mechanisms.
• Drugs that enhance GABA function (particularly in the amygdala) indirectly via modulatory sites on the GABA receptor for barbiturates, BDZs, and neuroactive steroids reduce anxiety and seizures and produce sedation. Manipulation of neurosteroid synthesis and manipulation of degradation represent potential new drug targets.
• Low levels of BDZ modulatory sites are associated with elevated anxiety in rodents and with panic disorder, PTSD, and GAD in human patients.
• Anxiety is modulated by 5-HT in a complex fashion. 5-HT_1A agonists binding to somatodendritic receptors in the raphe nucleus inhibit firing and release of 5-HT at projection sites causing anxiolysis. Local injection of 5-HT_1A agonists into the amygdala acting at postsynaptic receptors increases anxiety. Individuals with panic disorder or social anxiety disorder show reduced 5-HT_1A binding in the raphe.
• Exposure to uncontrollable (compared with controllable) stress leads to increased anxious behavior that can be prevented by lesioning the raphe nucleus. A high extracellular level of 5-HT during uncontrollable stress desensitizes the somatodendritic autoreceptors in the raphe nucleus and subsequently increases the firing of projection neurons and release of 5-HT in limbic regions.
• The anxiolytic drugs that block 5-HT reuptake (SSRIs) acutely increase synaptic 5-HT and may initially increase anxiety. Chronic administration over several weeks produces neuronal adaptations that are required for clinical effectiveness.
• The neurotrophic effect of 5-HT during fetal development is needed for normal development of the anxiety circuitry. People with a polymorphism of the 5-HT transporter gene who have higher prenatal 5-HT show increased emotionality. They also have reduced volume of the amygdala and ACC and weaker connections between these structures as adults.
• Dopaminergic projections to the amygdala that are activated by threatening stimuli reduce the inhibitory control from the mPFC and increase emotional responses.
• Stress increases phasic burst firing of select cells in VTA, causing increased release of DA, particularly in the nucleus accumbens. The acute increase in DA enhances the salience of the threat, but chronic activation in the absence of threat is associated with dysfunctional behavior.
• The tendency to express anxiety is determined by both genes and environmental events. Prenatal and early postnatal exposure to stress cause epigenetic changes that alter the stress circuitry and increase the behavioral and hormonal response to stressors in the adult. Stress-induced glucocorticoids damage the hippocampus and the PFC but increase synaptic connectivity in the amygdala.
• Stress-induced brain abnormalities depend on the timing and the developmental period. Significant gender differences in stress response are found in neural activity of the anxiety circuit, in HPA response, and in morphological differences after chronic stress.

Characteristics of Anxiety Disorders

• Anxiety disorders vary in symptoms, incidence, and time course, but all include high levels of anxiety.
• The chronic anxiety experienced in GAD is associated with enlargement and hyperactivity of the amygdala and too little inhibitory control by the PFC. Increasing inhibition with GABA agonists reduces symptoms.
• There is a genetic predisposition to sudden episodes of panic disorder. Dysregulation of adrenergic neurons in the autonomic nervous system and locus coeruleus may be involved. A genetic polymorphism of the NE transporter gene is associated with increased vulnerability to panic.
• In panic disorder, the volumes of the amygdala and the hippocampus are reduced. During a panic attack, neural activity is increased in the amygdala, cingulate cortex, and insula and is reduced in the PFC.
• The individual with panic disorder experiences intense fearfulness with autonomic activation as well as anticipatory anxiety over the concern of being observed having an attack in a public place.
• Phobias involve irrational fears of objects or situations and are best treated with behavioral desensitization.
• Social anxiety disorder involves extreme fear of being evaluated in public and is associated with increased blood flow in the amygdala during challenge that normalizes after treatment.
• Not all trauma victims develop PTSD. Genetic vulnerability factors increase the probability that PTSD will occur following a less intense traumatic event. Other vulnerability factors include female gender, lack of social support after the trauma, and a history of chronic stress or abuse.
• Low blood cortisol is a marker of vulnerability for PTSD and may be due to a hypersensitive negative feedback mechanism.
• Neuroimaging shows a reduction in hippocampal volume in patients with PTSD. It may be a consequence of trauma itself rather than of PTSD. Other reserchers have found that the reduction preceded the trauma-induced PTSD, making it a vulnerability factor.
• In PTSD the amygdala shows increased neural activity, and the anterior cingulate and the medial PFC are less active and fail to inhibit the limbic structures.
• OCD is a severe, chronic psychiatric problem characterized by recurring, persistent, intrusive thoughts and repetitive rituals. The irrational acts of OCD must be performed to prevent extreme anxiety.
• The caudate nucleus has a central role in the pathophysiology of OCD and is one component in the dysfunctional cortico-striatal-thalamic-cortical loop.
• Animal models of OCD can be naturalistic or produced by genetic manipulations. Optogenetics and chemogenetics provide the opportunity to dissect the neural circuits more precisely than previously. Well-designed behavioral tasks using laboratory animals are needed to ensure that therapeutic drug testing in the lab can translate to clinical application in humans.

Drugs for Treating Anxiety, OCD, and PTSD

• Anxiolytics are sedative–hypnotics that belong to the larger class of CNS depressants.
• Dose-dependent effects of sedative–hypnotics begin with reduction in anxiety and progress through stages of increasing sedation, incoordination, sleep, coma, and death.
• Sedative–hypnotics increase GABA-induced Cl^– current into the cell, causing enhanced hyperpolarization and inhibition of many cells.
• BDZs enhance GABA inhibition but have no effect of their own on chloride conductance. Flumazenil is a BDZ receptor competitive antagonist that reduces BDZ effects but has no effect on GABA-induced hyperpolarization. Since BDZs shift the GABA dose–response curve to the left but do not increase the maximum GABA response, they are safer than barbiturates and other sedative–hypnotics.
• Barbiturates increase GABA-induced Cl^– conductance and directly open the Cl^– channel without GABA.
• The barbiturates are ultrashort-acting, short/intermediate-acting, and long-acting drugs, depending on their lipid solubility, which determines the rate of penetration into the brain and the extent of redistribution to drug depots and liver metabolism. Duration of action determines their clinical uses.
• Side effects of barbiturates include altered sleep architecture, mental clouding and cognitive impairment, low therapeutic index, rapid tolerance and cross-tolerance, physical dependence, and dangerous withdrawal.
• BDZs are prescribed on the basis of onset and duration. Lipid solubility determines onset. Redistribution to depots and metabolism determine duration. Many have active metabolites, making them long acting.
• Therapeutic uses of BDZs include presurgical anesthesia, anxiolysis, sleep induction, muscle relaxation, seizure control, and termination of alcohol withdrawal.
• Advantages of BDZs compared with other sedative–hypnotics include high therapeutic index, availability of a competitive antagonist to reverse overdose, reduced tolerance and drug interactions, less physical dependence and milder withdrawal, less reinforcement value, and lower abuse potential. Fatalities do not occur unless a BDZ is combined with another sedative–hypnotic.
• Because of the risk of abuse, most clinical guidelines recommend BDZ use only for short-term treatment.
• Multiple forms of the GABA_A receptor subunits provide targets in drug development aimed at increasing therapeutic selectivity and reducing side effects. Drugs selective for the α2 GABA_A receptor show anxiolysis without sedation in animal studies, but not in clinical trials. The α1 GABA_A receptor is likely to play a significant role in sedation, as well as BDZ reinforcement, predicting abuse potential. New drugs targeting the α2 GABA_A receptor with minimal activity at α1 GABA_A receptors may be anxiolytic with less risk of abuse.
• Allopregnanolone and other similar neurosteroids bind to the neurosteroid modulatory site on GABA_A receptors and enhance the function of GABA, causing antianxiety effects. Synthetic allopregnanolone analogs reduce anxiety without sedation. Drugs that increase the synthesis of allopregnanolone by targeting the rate-limiting step (i.e., the transport of cholesterol into mitochondria) have anxiolytic properties without some of the usual adverse effects of anxiolytics, such as sedation, memory impairment, and signs of withdrawal.
• Buspirone is an anxiolytic that does not enhance GABA action but is a partial agonist at 5-HT_1A receptors. Its advantages over BDZs are that it reduces both anxiety and depression without sedation or mental clouding, it does not enhance other sedative–hypnotics, and it has no withdrawal syndrome or abuse potential.
• The disadvantages of buspirone are its slow onset of anxiolytic effects; its ineffectiveness for relieving alcohol or barbiturate withdrawal, insomnia, or seizures; and its lack of muscle relaxant effects.
• Antidepressants, including tricyclic antidepressants, MAOIs, and SSRIs, may be used to reduce the anxiety accompanying depression. Some antidepressants relieve symptoms of specific anxiety disorders.
• SSRIs are a drug class of first choice for anxiety because they have a high therapeutic index, and low abuse potential. However, SSRIs take 4 to 6 weeks to show effectiveness following neural adaptations to chronic use. Side effects that are problematic include increased anxiety and insomnia and sexual dysfunction. Withdrawal symptoms are common following drug cessation.