Background
Anxiety disorders are common psychiatric disorders. Many patients with anxiety disorders experience physical symptoms related to anxiety and subsequently visit their primary care providers. Despite the high prevalence rates of these anxiety disorders, they often are underrecognized and undertreated clinical problems. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) classifies the anxiety disorders into the following categories:
- Anxiety due to a general medical condition
- Substance-induced anxiety disorder
- Generalized anxiety disorder
- Acute stress disorder
- Adjustment disorder with anxious features
- Social phobia, also referred to as social anxiety disorder
- Specific phobia, also referred to as simple phobia - Specific phobias have been further broken down by the DSM-IV-TR to include animal type, such as fear of dogs (cynophobia), cats (ailurophobia), bees (apiphobia), spiders (arachnophobia), snakes (ophidiophobia); natural environment type, such as fear of heights (acrophobia), water (hydrophobia), or thunderstorms (astraphobia); blood injection/injury type, such as fear of pain (algophobia) or of being beaten (rhabdophobia); situational type, such as fear of flying (pteromerhanophobia), elevators, or enclosed spaces; and other type
Anxiety disorders appear to be caused by an interaction of biopsychosocial factors, including genetic vulnerability, which interact with situations, stress, or trauma to produce clinically significant syndromes. (See Pathophysiology and Etiology.)
Symptoms vary depending on the specific anxiety disorder. (See Clinical Presentation.)
Treatment usually consists of a combination of pharmacotherapy (see Medication) and/or psychotherapy. (See Treatment Strategies and Management.)
Anatomy
The brain circuits and regions associated with anxiety disorders are beginning to be understood with the development of functional and structural imaging. The brain amygdala appears key in modulating fear and anxiety. Patients with anxiety disorders often show heightened amygdala response to anxiety cues. The amygdala and other limbic system structures are connected to prefrontal cortex regions. Hyperresponsiveness of the amygdala may relate to reduced activation thresholds when responding to perceived social threat.[1, 2] Prefrontal-limbic activation abnormalities have been shown to reverse with clinical response to psychologic or pharmacologic interventions.
Pathophysiology
In the central nervous system (CNS), the major mediators of the symptoms of anxiety disorders appear to be norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid (GABA). Other neurotransmitters and peptides, such as corticotropin-releasing factor, may be involved. Peripherally, the autonomic nervous system, especially the sympathetic nervous system, mediates many of the symptoms.[3]
Positron emission tomography (PET) scanning has demonstrated increased flow in the right parahippocampal region and reduced serotonin type 1A receptor binding in the anterior and posterior cingulate and raphe of patients with panic disorder.[4] MRI has demonstrated smaller temporal lobe volume despite normal hippocampal volume in these patients.[5] The CSF in studies in humans shows elevated levels of orexin, also known as hypocretin, which is thought to play an important role in the pathogenesis of panic in rat models.[6]
Research and treatment trials suggest that abnormalities in serotonin neurotransmission in the brain are meaningfully involved in obsessive-compulsive disorder (OCD). This is strongly supported by the efficacy of serotonin reuptake inhibitors in the treatment of OCD.[7, 8]
Evidence also suggests abnormalities in dopaminergic transmission in at least some cases of OCD. In some cohorts, Tourette disorder (also known as Tourette syndrome) and multiple chronic tics genetically co-vary with OCD in an autosomal dominant pattern. OCD symptoms in this group of patients show a preferential response to a combination of selective serotonin reuptake inhibitors (SSRIs) and antipsychotics.[9]
Functional imaging studies in OCD have demonstrated some reproducible patterns of abnormality. Specifically, magnetic resonance imaging (MRI) and PET scanning have shown increases in blood flow and metabolic activity in the orbitofrontal cortex, limbic structures, caudate, and thalamus, with a trend toward right-sided predominance. In some studies, these areas of overactivity have been shown to normalize following successful treatment with either SSRIs or cognitive-behavioral therapy (CBT).[10]
These findings suggest the hypothesis that the symptoms of OCD are driven by impaired intracortical inhibition of specific orbitofrontal-subcortical circuitry that mediates strong emotions and the autonomic responses to those emotions. (Similar abnormalities of inhibition are observed in Tourette disorder, with a postulated abnormal modulation of basal ganglia activation.) Cingulotomy, a neurosurgical intervention sometimes used for severe and treatment-resistant OCD, interrupts this circuit (see Treatment).
More recently, attention has focused on glutamatergic abnormalities in OCD.[11] Although modulated by serotonin and other neurotransmitters, the synapses in the cortico-striato-thalamo-cortical circuits thought to be centrally involved in the pathology of OCD principally employ the neurotransmitters glutamate and GABA.
The fact that obsessive-compulsive symptoms seem to often take very stereotypic forms has led some to hypothesize that the pathologic disturbance causing OCD may be disinhibiting and exaggerating some built-in behavioral potential that we have, which under other circumstances might have an adaptive function (eg, primate grooming rituals).
Etiology
Anxiety disorders in general
The first consideration is the possibility that anxiety is due to a known or unrecognized medical condition. Substance-induced anxiety disorder (over-the-counter medications, herbal medications, substances of abuse) is a diagnosis that often is missed.
Genetic factors significantly influence risk for many anxiety disorders. Environmental factors such as early childhood trauma can also contribute to risk for later anxiety disorders. The debate whether gene or environment is primary in anxiety disorders has evolved to a better understanding of the important role of the interaction between genes and environment.[12] Some individuals appear resilient to stress, while others are vulnerable to stress, which precipitates an anxiety disorder.
Most presenting anxiety disorders are functional psychiatric disorders. Psychological theories range from explaining anxiety as a displacement of an intrapsychic conflict (psychodynamic models) to conditioning (learned) paradigms (cognitive-behavioral models). Many of these theories capture portions of the disorder.
The psychodynamic theory has explained anxiety as a conflict between the id and ego. Aggressive and impulsive drives may be experienced as unacceptable resulting in repression. These repressed drives may break through repression, producing automatic anxiety. The treatment uses exploration with the goal of understanding the underlying conflict. Cognitive theory has explained anxiety as the tendency to overestimate the potential for danger. Patients with anxiety disorder tend to imagine the worst possible scenario and avoid situations they think are dangerous, such as crowds, heights, or social interaction.
Panic disorder
Panic disorder appears to be a genetically inherited neurochemical dysfunction that may involve autonomic imbalance; decreased GABA-ergic tone[13] ; allelic polymorphism of the catechol-O-methyltransferase (COMT) gene; increased adenosine receptor function; increased cortisol[14] ; diminished benzodiazepine receptor function; and disturbances in serotonin,[15] serotonin transporter (5-HTTLPR)[16] and promoter (SLC6A4) genes,[17] norepinephrine, dopamine, cholecystokinin, and interleukin-1-beta.[18] Some theorize that panic disorder may represent a state of chronic hyperventilation and carbon dioxide receptor hypersensitivity.[7] Some epileptic patients have panic as a manifestation of their seizures. Genetic studies suggest that the chromosomal regions 13q, 14q, 22q, 4q31-q34, and probably 9q31 may be associated with the heritability of panic disorder phenotype.[19]
The cognitive theory regarding panic is that patients with panic disorder have a heightened sensitivity to internal autonomic cues (eg, tachycardia).
Triggers of panic can include the following:
- Injury (eg, accidents, surgery)
- Illness
- Interpersonal conflict or loss
- Use of cannabis (can be associated with panic attacks, perhaps because of breath-holding)[20]
- Use of stimulants, such as caffeine, decongestants, cocaine, and sympathomimetics (eg, amphetamine, MDMA [“ecstasy”])[21]
- Certain settings, such as stores and public transportation (especially in patients with agoraphobia)
- Sertraline can induce panic in previously asymptomatic patients.[22]
- The SSRI discontinuation syndrome can induce symptoms similar to those experienced by panic patients.
In experimental settings, symptoms can be elicited in people with panic disorder by hyperventilation, inhalation of carbon dioxide, caffeine consumption, or intravenous infusions of hypertonic sodium lactate or hypertonic saline,[23] cholecystokinin, isoproterenol, flumazenil[24] , or naltrexone.[25] The carbon dioxide inhalation challenge is especially provocative of panic symptoms in smokers.[26]
Posttraumatic stress disorder
PTSD is caused by experiencing, witnessing, or being confronted with an event involving serious injury, death, or threat to the physical integrity of an individual, along with a response involving helplessness and/or intense fear or horror. The more severe the trauma and the more intense the acute stress symptoms, the higher the risk for PTSD. When these events involve an individual with a physiologic vulnerability based on genetic (inherited) contributions and other personal characteristics, PTSD results.
Researchers have identified factors that interact to influence vulnerability to developing PTSD.[27] [28] These factors include the following:
- The characteristics of the trauma exposure itself, such as proximity to, severity of, and duration of exposure to the trauma
- The characteristics of the individual, such as prior exposure to trauma, childhood adversity (eg, separation from parents), preexisting anxiety or depression, and sex (women are at greatest risk for many of the most common assertive traumas)
- Posttrauma factors, such as availability of social support, emergence of avoidance or numbing, hyperarousal, and reexperiencing symptoms (for reexperiencing symptoms specifically, a pilot monozygotal twin study shows that patients with PTSD have impaired extinction of novel conditioned fear stimuli[29] )
Obsessive-compulsive disorder
The cause of OCD is not known; however, genetic factors, infections, other neurologic conditions, stress, and interpersonal relationships have all been shown to be relevant.
Twin studies have supported strong heritability for OCD, with a genetic influence of 45-65% in studies in children, and 27-47% in adults.[30] Monozygotic twins may be strikingly concordant for OCD (80-87%), compared with 47-50% concordance in dizygotic twins.[31] Several genetic studies have supported linkages to a variety of serotonergic, dopaminergic, and glutamatergic genes.[32, 33, 34, 35, 36] Other genes putatively linked to OCD have included those coding for catechol-O-methyltransferase (COMT), monoamine oxidase-A (MAO-A), brain-derived neurotrophic factor (BDNF), myelin oligodendrocyte glycoprotein (MOG), GABA-type B-receptor 1, and the mu opioid receptor, but these must be considered provisional associations at this time. In some cohorts, OCD, attention deficit hyperactivity disorder (ADHD), and Tourette disorder/tic disorders co-vary in an autosomal dominant fashion with variable penetrance.
Case reports have been published of OCD with and without tics arising in children and young adults following acute group A streptococcal infections. Fewer reports cite herpes simplex virus as the apparent precipitating infectious event. It has been hypothesized that these infections trigger a CNS autoimmune response that results in neuropsychiatric symptoms (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections [PANDAS]). A number of the poststreptococcal cases have reportedly improved following treatment with antibiotics.
Rare reports exist of OCD presenting as a manifestation of neurologic insults such as brain trauma, stimulant abuse, and carbon monoxide poisoning.
OCD symptoms can worsen with stress; however, stress does not appear to be an etiologic factor.
OCD symptoms can interact negatively with interpersonal relationships, and families can become involved with the illness in a counterproductive way (eg, a patient with severe doubting obsessions may constantly ask reassurance for irrational fears from family members or significant others; constantly providing this can inhibit the patient from making attempts to work on their behavioral disturbances). Parenting style or upbringing does not appear to be a causative factor in OCD.
Social phobia (social anxiety disorder)
Genetic factors seem to play a role in social phobia. Based on family and twin studies, the risk for social phobia appears to be moderately heritable.[37, 38]
Social phobia can be initiated by traumatic social experience (eg, embarrassment) or by social skills deficits that produce recurring negative experiences. A hypersensitivity to rejection, perhaps related to serotonergic or dopaminergic dysfunction, is present. Current thought is that social phobia appears to be an interaction between biological and genetic factors and environmental events.
A psychoanalyst would likely conceptualize social anxiety as a symptom of a deeper conflict—for instance, low self-esteem or unresolved conflicts with internal objects. A behaviorist would see phobia as a learned, conditioned response resulting from a past association with a situation with negative emotional valence at the time of association (eg, social situations are avoided because intense anxiety was originally experienced in that setting). Even if no danger is posed in most social encounters, an avoidance response has been linked to these situations. Treatment from this perspective aims to weaken and eventually separate the specific response from the stimulus.
Specific (simple) phobia
Genetic factors seem to play a role in specific phobia as well (eg, in blood-injury phobia), and the risk for such phobias also seems to be moderately heritable.[37] In addition, specific phobia can be acquired by conditioning, modeling, or traumatic experience.
Agoraphobia may be the result of repeat, unexpected panic attacks, which, in turn, may be linked to cognitive distortions, conditioned responses, and/or abnormalities in noradrenergic, serotonergic, or GABA-related neurotransmission.
Epidemiology
United States statistics
Social phobia is the most common anxiety disorder; it has an early age of onset—by age 11 years in about 50% and by age 20 years in about 80% of individuals that have the diagnosis—and it is a risk factor for subsequent depressive illness and substance abuse.[39]
Once believed to be rare, OCD was found to have a lifetime prevalence in the range of 1.7-4%. Discovery of effective treatments and education of patients and health care providers have significantly increased the identification of individuals with OCD over the past decade.
According to 2 major studies in the United States—the Epidemiological Catchment Area (ECA) study[40] and the National Comorbidity Survey (NCS) study[41] —in conjunction with other studies, the estimated lifetime prevalence rates for individual anxiety disorders are 2.3-2.7% for panic disorder, 4.1-6.6% for generalized anxiety disorder, 2.3-2.6% for OCD, 1-9.3% for PTSD, and 2.6-13.3% for social phobia.
Further, the NCS reported the following lifetime (and 30-day) prevalence estimates: 6.7% (and 2.3%) for agoraphobia, 11.3% (and 5.5%) for simple (ie, specific) phobia, and 13.3% (and 4.5%) for social phobia.[42, 43]
International statistics
The prevalence of specific anxiety disorders appears to vary between countries and cultures. A cross-national study of the prevalence of panic disorder found lifetime prevalence rates ranging from 0.4% in Taiwan to 2.9% in Italy. A cross-cultural study of the prevalence of OCD found lifetime prevalence rates ranging from 0.7% in Taiwan to 2.5% in Puerto Rico.
In some Far East cultures, individuals with social phobia may develop fears of being offensive to others rather than fears of being embarrassed.
Prevalence of anxiety disorders by race
The ECA study found no difference in rates of panic disorder among white, African American, or Hispanic populations in the United States. Some studies have found higher rates of PTSD in minority populations. Some of this association may be due to higher rates of specific traumatic events (ie, assault) in minority populations.
Sex ratio for anxiety disorders
The female-to-male ratio for any lifetime anxiety disorder is 3:2 (see the image below).
Anxiety. Chart showing the female-to-male sex ratio for anxiety disorders. Adapted from Kessler et al, 1994. Age distribution for anxiety disorders
Most anxiety disorders begin in childhood, adolescence, and early adulthood (see the image below). Separation anxiety is an anxiety disorder of childhood that often includes anxiety related to going to school. This disorder may be a precursor for adult anxiety disorders.
Anxiety. Age of onset for anxiety disorders based on specific anxiety disorder type. Panic disorder demonstrates a bimodal age of onset in the NCS study in the age groups of 15-24 years and 45-54 years. The age of onset for OCD appears to be in the mid 20s to early 30s.
Most social phobias begin before age 20 years (median age at illness onset, 16 years.[42] )
Agoraphobia usually begins in late adolescence to early adulthood (median age at illness onset, 29 years.[42] )
In general, specific phobia appears earlier than social phobia or agoraphobia. The age of onset depends on the particular phobia. For example, animal phobia is most common at the elementary school level and appears at a mean age of 7 years; blood phobia appears at a mean age of 9 years; dental phobia appears at a mean age of 12 years; and claustrophobia appears at a mean age of 20 years. Most simple (specific) phobias develop during childhood (median age at illness onset, 15 y).[42] ) and eventually disappear. Those that persist into adulthood rarely go away without treatment.
New-onset anxiety symptoms in older adults should prompt a search for an unrecognized general medical condition, a substance abuse disorder, or major depression with secondary anxiety symptoms.
Prognosis
Anxiety disorders have high rates of comorbidity with major depression and alcohol and drug abuse. Some of the increased morbidity and mortality associated with anxiety disorders may be related to this high rate of comorbidity. Anxiety disorders may contribute to morbidity and mortality through neuroendocrine and neuroimmune mechanisms or by direct neural stimulation, (eg, hypertension or cardiac arrhythmia). Chronic anxiety may be associated with increased risk for cardiovascular morbidity and mortality.
Considerable evidence shows that social phobia (social anxiety disorder) results in significant functional impairment and decreased quality of life.[44, 45]
Severe anxiety disorders may be complicated by suicide, with or without secondary mood disorders (eg, depression). The Epidemiological Catchment Area study found that panic disorder was associated with suicide attempts (odds ratio = 18 compared with populations without psychiatric disorders). How much of the association of panic disorder with suicide is mediated through the association of panic disorder with mood and substance abuse disorders is unclear. Acute stress may play a role in producing suicidal behavior. The presence of any anxiety disorder, phobias included, in combination with a mood disorder appears to increase likelihood of suicide attempts compared with a mood disorder alone.[46] Suicide attempts can be precipitated by adverse life events such as divorce or financial disaster. The effects of acute stress in producing suicidal behavior are increased in those with underlying mood, anxiety, and substance abuse problems.
Phobias are highly comorbid. Most comorbid simple (specific) and social phobias are temporally primary, while most comorbid agoraphobia is temporally secondary. Comorbid phobias are generally more severe than pure phobias. Social phobia is also frequently comorbid with major depressive disorder and atypical depression, which results in increased disability.[45, 47] Despite evidence of impairment, only a minority of individuals with simple (specific) phobia ever seek professional treatment.
Interestingly, in clinical samples, over 95% of the patients reporting agoraphobia also present with panic disorder, while in epidemiologic samples, simple agoraphobia appears to be more prevalent than panic disorder with agoraphobia.[48]
Patient Education
Education can be obtained through books, newsletters, support groups, and the Internet. Some useful Web sites are as follows:
- National Institute of Mental Health, Anxiety Disorders
- SAMHSA’s National Mental Health Information Center, Anxiety Disorders
- eMedicineHealth, Mental Health and Behavior Center and Anxiety Center
Family members should receive information about the effect of anxiety disorders on mood, behavior, and relationships. Family members can assist in care by reinforcing the need for medical treatment and supervision. Family members may also assist by providing a collaborative resource for monitoring the severity of the patient’s anxiety symptoms and response to treatment interventions.
Martinez RC, Ribeiro de Oliveira A, Brandão ML. Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray. Eur Neuropsychopharmacol. Nov 2007;17(11):717-24. [Medline]. [Full Text].
Keeton CP, Kolos AC, Walkup JT. Pediatric generalized anxiety disorder: epidemiology, diagnosis, and management. Paediatr Drugs. 2009;11(3):171-83. [Medline].
Freitas-Ferrari MC, Hallak JE, Trzesniak C, Filho AS, Machado-de-Sousa JP, Chagas MH. Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog Neuropsychopharmacol Biol Psychiatry. May 30 2010;34(4):565-80. [Medline].
Katerndahl DA, Talamantes M. A comparison of persons with early-versus late-onset panic attacks. J Clin Psychiatry. Jun 2000;61(6):422-7. [Medline].
Vythilingam M, Anderson ER, Goddard A, Woods SW, Staib LH, Charney DS. Temporal lobe volume in panic disorder--a quantitative magnetic resonance imaging study. Psychiatry Res. Aug 28 2000;99(2):75-82. [Medline].
Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S. A key role for orexin in panic anxiety. Nat Med. Jan 2010;16(1):111-5. [Medline].
Greist JH, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry. Jan 1995;52(1):53-60. [Medline].
Kobak KA, Greist JH, Jefferson JW, Katzelnick DJ, Henk HJ. Behavioral versus pharmacological treatments of obsessive compulsive disorder: a meta-analysis. Psychopharmacology (Berl). Apr 1998;136(3):205-16. [Medline].
Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. Jul 2006;11(7):622-32. [Medline].
Baxter LR Jr, Schwartz JM, Bergman KS, Szuba MP, Guze BH, Mazziotta JC, et al. Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry. Sep 1992;49(9):681-9. [Medline].
Pittenger C, Krystal JH, Coric V. Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. NeuroRx. Jan 2006;3(1):69-81. [Medline].
Tambs K, Czajkowsky N, Røysamb E, Neale MC, Reichborn-Kjennerud T, Aggen SH. Structure of genetic and environmental risk factors for dimensional representations of DSM-IV anxiety disorders. Br J Psychiatry. Oct 2009;195(4):301-7. [Medline].
Zwanzger P, Eser D, Nothdurfter C, Baghai TC, Möller HJ, Padberg F, et al. Effects of the GABA-reuptake inhibitor tiagabine on panic and anxiety in patients with panic disorder. Pharmacopsychiatry. Nov 2009;42(6):266-9. [Medline].
Wedekind D, Bandelow B, Broocks A, Hajak G, Rüther E. Salivary, total plasma and plasma free cortisol in panic disorder. J Neural Transm. 2000;107(7):831-7. [Medline].
Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci. Jan 21 2004;24(3):589-91. [Medline].
Lonsdorf TB, Rück C, Bergström J, Andersson G, Ohman A, Schalling M, et al. The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism. Prog Neuropsychopharmacol Biol Psychiatry. Nov 13 2009;33(8):1479-83. [Medline].
Strug LJ, Suresh R, Fyer AJ, Talati A, Adams PB, Li W, et al. Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry. Feb 2010;15(2):166-76. [Medline]. [Full Text].
Johnson MR, Lydiard RB, Ballenger JC. Panic disorder. Pathophysiology and drug treatment. Drugs. Mar 1995;49(3):328-44. [Medline].
Maron E, Hettema JM, Shlik J. Advances in molecular genetics of panic disorder. Mol Psychiatry. Jul 2010;15(7):681-701. [Medline].
Dannon PN, Lowengrub K, Amiaz R, Grunhaus L, Kotler M. Comorbid cannabis use and panic disorder: short term and long term follow-up study. Hum Psychopharmacol. Mar 2004;19(2):97-101. [Medline].
Schifano F, Di Furia L, Forza G, et al. MDMA (‘‘ecstasy'') consumption in the context of polydrug abuse: a report on 150 patients. Drug Alcohol Depend. Sep.
González-Berríos N. Sertraline-induced panic attack. Bol Asoc Med P R. Jan-Mar 2009;101(1):59-60. [Medline].
Molosh AI, Johnson PL, Fitz SD, Dimicco JA, Herman JP, Shekhar A. Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. Neuropsychopharmacology. May 2010;35(6):1333-47. [Medline].
Dratcu L. Panic, hyperventilation and perpetuation of anxiety. Prog Neuropsychopharmacol Biol Psychiatry. Oct 2000;24(7):1069-89. [Medline].
Esquivel G, Fernández-Torre O, Schruers KR, Wijnhoven LL, Griez EJ. The effects of opioid receptor blockade on experimental panic provocation with CO2. J Psychopharmacol. Nov 2009;23(8):975-8. [Medline].
Knuts IJ, Cosci F, Esquivel G, Goossens L, van Duinen M, Bareman M, et al. Cigarette smoking and 35% CO(2) induced panic in panic disorder patients. J Affect Disord. Jul 2010;124(1-2):215-8. [Medline].
Deykin EY. Posttraumatic Stress Disorder in Childhood and Adolescence: A Review. Medscape Mental Health [online]. 1999;Available at http://medscape.com.
Marshall RD, Pierce D. Implications of recent findings in posttraumatic stress disorder and the role of pharmacotherapy. Harv Rev Psychiatry. Jan-Feb 2000;7(5):247-56. [Medline].
Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J Psychiatr Res. Jun 2008;42(7):515-20. [Medline].
van Grootheest DS, Cath DC, Beekman AT, Boomsma DI. Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet. Oct 2005;8(5):450-8. [Medline].
Carey G, Gottesman I. Twin and family studies of anxiety, phobic, and obsessive disorders. In: Klein DF, Rabkin JG. Anxiety: New Research and Changing Concepts. New York: Raven Press; 2000.
Lochner C, Mogotsi M, du Toit PL, Kaminer D, Niehaus DJ, Stein DJ. Quality of life in anxiety disorders: a comparison of obsessive-compulsive disorder, social anxiety disorder, and panic disorder. Psychopathology. Sep-Oct 2003;36(5):255-62. [Medline].
Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch Gen Psychiatry. Jul 2006;63(7):769-76. [Medline].
Denys D, Van Nieuwerburgh F, Deforce D, Westenberg H. Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive-compulsive disorder in males. Eur Neuropsychopharmacol. Aug 2006;16(6):446-50. [Medline].
Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch Gen Psychiatry. Jul 2006;63(7):778-85. [Medline].
Lin PY. Meta-analysis of the association of serotonin transporter gene polymorphism with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. Apr 13 2007;31(3):683-9. [Medline].
Kendler KS, Karkowski LM, Prescott CA. Fears and phobias: reliability and heritability. Psychol Med. May 1999;29(3):539-53. [Medline].
Liebowitz MR, Klein DF. Fyer AJ, Mannuzza S, Chapman TF. A direct interview family study of social phobia. Arch Gen Psychiatry [serial online]. 1993;50:286-93. Available at http://ajp.psychiatryonline.org/cgi/content/full/155/1/90?ijkey=b6a6c8eaddea7996eacc6458e3d19c9474b64160.
Stein MB, Stein DJ. Social anxiety disorder. Lancet. Mar 29 2008;371(9618):1115-25. [Medline].
Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. Dec 1988;45(12):1094-9. [Medline].
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. Jan 1994;51(1):8-19. [Medline].
Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC. Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry. Feb 1996;53(2):159-68. [Medline].
Wittchen HU, Fehm L. Epidemiology, patterns of comorbidity, and associated disabilities of social phobia. Psychiatr Clin North Am. Dec 2001;24(4):617-41. [Medline].
Schneier FR, Heckelman LR, Garfinkel R, Campeas R, Fallon BA, Gitow A. Functional impairment in social phobia. J Clin Psychiatry. Aug 1994;55(8):322-31. [Medline].
Lochner C, Mogotsi M, du Toit PL, Kaminer D, Niehaus DJ, Stein DJ. Quality of life in anxiety disorders: a comparison of obsessive-compulsive disorder, social anxiety disorder, and panic disorder. Psychopathology. Sep-Oct 2003;36(5):255-62. [Medline].
Sareen J, Cox BJ, Afifi TO, de Graaf R, Asmundson GJ, ten Have M. Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. Arch Gen Psychiatry. Nov 2005;62(11):1249-57. [Medline]. [Full Text].
Matza LS, Revicki DA, Davidson JR, Stewart JW. Depression with atypical features in the National Comorbidity Survey: classification, description, and consequences. Arch Gen Psychiatry. Aug 2003;60(8):817-26. [Full Text].
American Psychiatric Association. American Psychiatric Association. In: Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association Press; 2000.
Helping Children and Adolescents Cope with Violence and Disasters. In: National Institute of Mental Health. NIH Publication No. 01-3518. Bethesda, Md: National Institute of Mental Health; 2001.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. Nov 1989;46(11):1006-11. [Medline].
First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Patient Edition (SCID-I/P, 11/2002 revision). New York: Biometrics Research Department, New York State Psychiatric Institute; November 2002.
Dickie EW, Brunet A, Akerib V, Armony JL. An fMRI investigation of memory encoding in PTSD: influence of symptom severity. Neuropsychologia. Apr 2008;46(5):1522-31. [Medline].
Kluge M, Schüssler P, Steiger A. Persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Psychiatry Clin Neurosci. Apr 2007;61(2):193-5. [Medline].
Cha C, Nock M. Emotional intelligence is a protective factor for suicidal behavior. J Am Acad Child Adolesc Psychiatry. Apr 2009;48(4):422-30. [Medline].
Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ. Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry. Mar 2009;166(3):302-10. [Medline].
Germain A, Shear MK, Hall M, Buysse DJ. Effects of a brief behavioral treatment for PTSD-related sleep disturbances: a pilot study. Behav Res Ther. Mar 2007;45(3):627-32. [Medline].
Raskind MA, Peskind ER, Hoff DJ, Hart KL, Holmes HA, Warren D. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. Apr 15 2007;61(8):928-34. [Medline].
de Beurs E, van Balkom AJ, Van Dyck R, Lange A. Long-term outcome of pharmacological and psychological treatment for panic disorder with agoraphobia: a 2-year naturalistic follow-up. Acta Psychiatr Scand. Jan 1999;99(1):59-67. [Medline].
Shear MK, Beidel DC. Psychotherapy in the overall management strategy for social anxiety disorder. J Clin Psychiatry. 1998;59 Suppl 17:39-46. [Medline].
[Best Evidence] [Guideline] Mayor S. NICE advocates computerised CBT. BMJ. Mar 4 2006;332(7540):504. [Medline].
[Best Evidence] Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev. 2007;(1):CD001848. [Medline].
[Best Evidence] Ipser JC, Carey P, Dhansay Y, Fakier N, Seedat S, Stein DJ. Pharmacotherapy augmentation strategies in treatment-resistant anxiety disorders. Cochrane Database Syst Rev. Oct 18 2006;CD005473. [Medline].
Walkup J, Labellarte M, Riddle MA, Pine DS, Greenhill L, Fairbanks J, et al. Treatment of pediatric anxiety disorders: an open-label extension of the research units on pediatric psychopharmacology anxiety study. J Child Adolesc Psychopharmacol. Fall 2002;12(3):175-88. [Medline].
Toneatto T, Nguyen L. Does mindfulness meditation improve anxiety and mood symptoms? A review of the controlled research. Can J Psychiatry. Apr 2007;52(4):260-6. [Medline].
American Psychiatric Association (APA). Practice guideline for the treatment of patients with panic disorder. 2nd ed. Washington (DC): American Psychiatric Association (APA); 2009 Jan. Available from the PsychiatryOnline website. Available at http://www.psychiatryonline.com/pracGuide/pracGuideChapToc_9.aspx. Accessed June 15, 2011.
Celexa (citalopram hydrobromide) [package insert]. St. Louis, Missouri: Forest Pharmaceuticals, Inc; August, 2011. [Full Text].
US Food and Drug Administration. Celexa (citalopram hydrobromide): Drug safety communication – abnormal heart rhythms associated with high doses. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm269481.htm. Accessed August 24, 2011.
Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs. 2009;23(5):427-52. [Medline].
Kim JE, Yoon SJ, Kim J, Jung JY, Jeong HS, Cho HB, et al. Efficacy and tolerability of mirtazapine in treating major depressive disorder with anxiety symptoms: an 8-week open-label randomised paroxetine-controlled trial. Int J Clin Pract. Mar 2011;65(3):323-9. [Medline].
Sinclair LI, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. Jun 2009;194(6):483-90. [Medline].
Rodriguez BF, Weisberg RB, Pagano ME, Machan JT, Culpepper L, Keller MB. Mental health treatment received by primary care patients with posttraumatic stress disorder. J Clin Psychiatry. Oct 2003;64(10):1230-6. [Medline].
Högberg G, Pagani M, Sundin O, Soares J, Aberg-Wistedt A, Tärnell B. Treatment of post-traumatic stress disorder with eye movement desensitization and reprocessing: outcome is stable in 35-month follow-up. Psychiatry Res. May 30 2008;159(1-2):101-8. [Medline].
Ponniah K, Hollon SD. Empirically supported psychological treatments for adult acute stress disorder and posttraumatic stress disorder: a review. Depress Anxiety. 2009;26(12):1086-109. [Medline].
Litz BT, Engel CC, Bryant RA, Papa A. A randomized, controlled proof-of-concept trial of an Internet-based, therapist-assisted self-management treatment for posttraumatic stress disorder. Am J Psychiatry. Nov 2007;164(11):1676-83. [Medline].
Foa EB, Wilson R. Stop Obsessing!: How to Overcome Your Obsessions and Compulsions. Revis ed. New York: Bantam Dell; 2001.
Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. Sep 1 2005;58(5):424-8. [Medline].
Greenberg WM, Benedict MM, Doerfer J, Perrin M, Panek L, Cleveland WL. Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults. J Psychiatr Res. Mar 2009;43(6):664-70. [Medline].
Grayson J. Freedom From Obsessive Compulsive Disorder: A Personalized Recovery Program for Living With Uncertainty. New York: Berkley Publishing Group; 2004.
Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. Jul 2007;164(7 Suppl):5-53. [Medline]. [Full Text].
Jung HH, Kim CH, Chang JH, Park YG, Chung SS, Chang JW. Bilateral anterior cingulotomy for refractory obsessive-compulsive disorder: Long-term follow-up results. Stereotact Funct Neurosurg. 2006;84(4):184-9. [Medline].
Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology. Nov 2006;31(11):2384-93. [Medline].
Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. Nov 13 2008;359(20):2121-34. [Medline].
[Best Evidence] Barlow JH, Ellard DR, Hainsworth JM, Jones FR, Fisher A. A review of self-management interventions for panic disorders, phobias and obsessive-compulsive disorders. Acta Psychiatr Scand. Apr 2005;111(4):272-85. [Medline].
Lewis C, Pearce J, Bisson JI. Efficacy, cost-effectiveness and acceptability of self-help interventions for anxiety disorders: systematic review. Br J Psychiatry. Jan 2012;200:15-21. [Medline].
Lydiard RB. The role of drug therapy in social phobia. J Affect Disord. Sep 1998;50 Suppl 1:S35-9. [Medline].
Van Ameringen M, Allgulander C, Bandelow B, Greist JH, Hollander E, Montgomery SA, et al. WCA recommendations for the long-term treatment of social phobia. CNS Spectr. Aug 2003;8(8 Suppl 1):40-52. [Medline].
Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, et al. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry. Dec 1998;55(12):1133-41. [Medline]. [Full Text].
Allgulander C. Paroxetine in social anxiety disorder: a randomized placebo-controlled study. Acta Psychiatr Scand. Sep 1999;100(3):193-8. [Medline].
Stein MB, Fyer AJ, Davidson JR, Pollack MH, Wiita B. Fluvoxamine treatment of social phobia (social anxiety disorder): a double-blind, placebo-controlled study. Am J Psychiatry. May 1999;156(5):756-60. [Medline].
[Best Evidence] Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: systematic review. Br J Psychiatry. Apr 2006;188:305-12. [Medline].
Ayala ES, Meuret AE, Ritz T. Treatments for blood-injury-injection phobia: a critical review of current evidence. J Psychiatr Res. Oct 2009;43(15):1235-42. [Medline].
Rothbaum BO, Anderson P, Zimand E, Hodges L, Lang D, Wilson J. Virtual reality exposure therapy and standard (in vivo) exposure therapy in the treatment of fear of flying. Behav Ther. Mar 2006;37(1):80-90. [Medline]. [Full Text].
Practice guideline for the treatment of patients with panic disorder. Work Group on Panic Disorder. American Psychiatric Association. Am J Psychiatry. May 1998;155(5 Suppl):1-34. [Medline].
Pohl RB, Wolkow RM, Clary CM. Sertraline in the treatment of panic disorder: a double-blind multicenter trial. Am J Psychiatry. Sep 1998;155(9):1189-95. [Medline]. [Full Text].
Michelson D, Lydiard RB, Pollack MH, Tamura RN, Hoog SL, Tepner R, et al. Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group. Am J Psychiatry. Nov 1998;155(11):1570-7. [Medline].
Uhlenhuth EH, Balter MB, Ban TA, Yang K. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997. Depress Anxiety. 1999;9(3):107-16. [Medline].
Herrera-Arellano A, Jiménez-Ferrer E, Zamilpa A, Morales-Valdéz M, García-Valencia CE, Tortoriello J. Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam. Planta Med. Jul 2007;73(8):713-7. [Medline].
Komossa K, Depping AM, Meyer M, Kissling W, Leucht S. Second-generation antipsychotics for obsessive compulsive disorder. Cochrane Database Syst Rev. Dec 8 2010;12:CD008141. [Medline].
Advisory Committee FDA. SEROQUEL XR for the Treatment of Patients with either Major Depressive Disorder or Generalized Anxiety Disorder. FDA; [Full Text].
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Association; 2000.
Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR. Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study. Br J Psychiatry. Jul 1999;175:17-22. [Medline].
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