Generalized Anxiety Disorder

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Diagnosis and reasoning

This 26 year old student has presented with numerous signs and symptoms suggestive of anxiety, in association with chronic diarrhea. Note that the latter has already been thoroughly investigated, with no obvious organic or functional cause found; thus, it might very well be yet another manifestation of anxiety (which is not an uncommon finding). A closer look at her history brings up some important points: - Her symptoms have lasted for more than 6 months, have been present on multiple occasions, and cover multiple domains (i.e. family, finances, and personal security) - She finds herself worrying constantly - Her studies have been affected negatively - Restlessness, fatigability, difficulty in concentrating, and sleep disturbances are present - There are no features suggestive of panic episodes, phobic disorder, obsessive compulsive behavior; nor does she exhibit suicidal ideation, depressive symptoms, or features suggestive of a mood or psychotic disorder. - No signs and symptoms suggestive of organic disease are present When considered together, the above fulfil the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for generalized anxiety disorder (GAD). Note that it is still important TO perform some basic investigations, so as to definitively exclude an organic cause. In this regard, a complete blood count is normal, as are inflammatory marker levels, making an infectious or inflammatory etiology less likely; metabolic derangements are excluded by the normal metabolic profile. While hyperthyroidism can also present in this manner, this has already been excluded by the gastroenterologist; repeat testing is probably unnecessary. It is also crucial to appreciate that use of, and withdrawal from certain recreational drugs can result in similar symptoms; however, a urinary drug screen is normal as well. Thus, the final diagnosis is GAD indeed. Cognitive behavioural therapy is the mainstay of treatment in these patients, and should be commenced as soon as possible; this should be combined with a selective serotonin reuptake inhibitor (such as Paroxetine). Benzodiazepines can also be administered for quick, short-term symptomatic relief. However, they should not be used in the long-term, due to their high side effect profile. Note that exposure and response prevention is a form of psychotherapy used in the treatment of obsessive compulsive disorder and certain phobic disorders. It is not indicated in individuals with GAD.


Generalized anxiety disorder (GAD) is characterized by excessive, uncontrollable, and irrational worry, which interferes with daily functions. In the United States alone, the condition is estimated to have a lifetime prevalence of between 4.1% to 6.6%, with around 6.8 million adults affected each year. Women are affected twice as often as men. Studies have revealed that the unnatural anxiety in these patients is associated with neurobiological irregularities involving the γ-aminobutyric acid [GABA] and serotonin systems. In addition, in these individuals, the connections between the amygdala, basolateral complex and adjacent areas seem less distinct and show decreased connectivity, resulting in dysfunctional processing of anxiety. Key risk factors for GAD include female gender, childhood trauma, chronic illness, stress, certain personality types (eg: borderline), substance abuse, and genetics. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), GAD is categorized as an anxiety disorder; the diagnostic criteria include, - Extensive anxiety and worry for more than 6 months, regarding multiple events and activities - Difficulty in controlling worry - Anxiety associated with 3 or more of the following symptoms: restlessness or feeling on edge; easy fatigability; difficulty in concentrating; irritability; muscle tension; sleep disturbances - The anxiety and physical symptoms cause significant distress or impairment in social, occupational or other areas of functioning - The focus of anxiety is not confined to features of another disorder such as social phobia, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), etc. - The disturbance is not due to the direct effect of a substance or a general medical condition and does not occur during a mood disorder, psychotic disorder or a pervasive development disorder. Note that the signs and symptoms of GAD can vary; these typically include constant worrying about small concerns, the mind going blank, restlessness, fatigability, irritability, muscle tension, trembling, a feeling of being easily startled, difficulty in sleeping, sweating, nausea, diarrhea, lightheadedness, shortness of breath, and a rapid heart rate. There are no laboratory tests to diagnose GAD; investigations are mainly of use in excluding anxiety associated with a medical condition, or substance abuse. Key tests include a complete blood count (CBC), inflammatory markers such as an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), a complete metabolic profile, thyroid profile, urinalysis and urine drug screen. Both psychotherapy and pharmacotherapy help reduce the anxiety associated with the condition; however, the former is considered to be more effective in the long term. To understand this, one needs to appreciate that GAD has many negative psychological components including cognitive avoidance, intolerance of uncertainty, negative problem orientation, ineffective problem solving, poor understanding of emotions, emotional processing, emotional hyperarousal, maladaptive emotion management and regulation, interpersonal issues, experiential avoidance and behavioural restriction. Thus, cognitive behavioural therapy (CBT), and acceptance and commitment therapy are the two key forms of psychotherapy of use in these individuals. CBT is key to addressing the above cognitive and emotional aspects of GAD via self monitoring, relaxation techniques, self-control desensitisation, gradual stimulus control, cognitive restructuring, worry-outcome monitoring, present moment monitoring, and emotional skills training. Acceptance and commitment therapy on the other hand, establishes mindfulness and acceptance skills for responding to uncontrollable events, thus helping the individual in accomplishing their personal goals. Note that motivational interviewing and intolerance of uncertainty therapy are two novel treatment modalities which can be used either as stand-alone treatments, or as adjuvants to CBT. Antidepressants are the first line pharmacological treatment option for GAD; selective serotonin reuptake inhibitors (SSRIs) are considered the drug of choice due to their high efficacy and low side effect profile. Benzodiazepines were the preferred drugs in the past, but are now not recommended for long-term use, given their association with dependence, tolerance, withdrawal syndrome and psychomotor, memory and cognitive impairment. Note that pregabalin and gabapentin, novel drugs which act on voltage-dependant calcium channels to decrease the release of neurotransmitters such as glutamate, noradrenaline and substance P, have also proven to be efficacious in the treatment of GAD. GAD is associated with high rates of comorbidities, including major depression, alcohol and drug abuse; these might account for the high morbidity and mortality associated with the disease. In addition, multiple studies have revealed that both direct and indirect contributions via neuroendocrine and neuroimmune mechanisms (eg: hypertension and cardiac arrhythmias) result in high rates of cardiovascular morbidity.

Take home messages

  1. Generalized anxiety disorder (GAD) is the commonest disorder affecting productivity in the United States.
  2. The diagnosis of GAD requires that symptoms should have been present for at least 6 months.
  3. Benzodiazepines offer rapid symptomatic relief, but should not be used in the long-term management of GAD.

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