User:Jrsauer/sandbox

Disclaimer: The following page includes notes regarding medications, complementary and alternative medications (CAMs) and other interventions that have been academically studied for their potential in treating generalized anxiety disorder (GAD) and constitute only a series of academic notes intended for a Wikipedia article (and coursework fulfillment) and neither an endorsement nor definitive statement regarding drug, CAM or efficacy of other modality in treating GAD, any other condition or use for any particular purpose. Please do not use this page for diagnosis or treatment of any medical or other disorder. Always consult a licensed physician for appropriate guidance on medical topics including any of the medications, CAMs or other modalities academically discussed herein.

Treatment

Traditional treatment modalities broadly fall into two (2) categories - i.e., psychotherapeutic and pharmacological intervention. In addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (CAMs), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. Treatment modalities can, and often are utilized concurrently so that an individual may pursue psychological therapy (i.e., psychotherapy) and pharmacological therapy.

Psychotherapy

Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behavior. Cognitive behavioral therapy (CBT) is widely regarded as the first-line psychological therapy for treating GAD. Additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. While individual and group settings are broadly both considered effective for treating GAD, individual therapy tends to promote longer-lasting engagement in therapy (i.e., lower attrition over time).

Psychodynamic therapy

Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. In the context of GAD, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defense mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. Accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in GAD in order to enable individuals to alter the subconscious practice of using worry as a defense mechanism and to thereby diminish GAD symptoms. Variations of psychotherapy include a near-term version of therapy, "short-term anxiety-provoking psychotherapy (STAPP).

Behavioral therapy

Behavioral therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g., one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioral therapy enables an individual to re-learn conditioned responses (behaviors) and to thereby challenge behaviors that have become conditioned responses fear and anxiety, and which have previously given rise to further maladaptive behaviors.

Cognitive therapy

Cognitive therapy (CT) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. Thus, CT involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e., cognitive distortions) with healthier thinking patterns (e.g., replacing the cognitive distortion of catastrophizing with a more productive pattern of thinking). Individuals in CT learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced.

Cognitive-Behavioral therapy

Cognitive-behavioral therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and which integrates the cognitive and behavioral therapeutic approaches. The objective of CBT is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. Because CBT involves the practice of worry and anxiety management, CBT includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. These interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitization.

Other forms of psychological therapy include:

• Relaxation techniques (e.g., relaxing imagery, meditational relaxation)
• Metacognitive Therapy (MCT): The objective of MCT is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy.
• Mindfulness based stress reduction (MBSR)
• Mindfulness based cognitive therapy (MBCT)
• Supportive therapy: This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness. Variations of active supportive therapy include Gestalt therapy, Transactional analysis and Counseling.

Pharmacotherapy

Historically, BZs were used prominently to treat anxiety starting in the 1970s but support for this use attenuated in view of the risk for dependence and tolerance to the medication. BZs can have a plurality of effects that made them an historically desirable option for treating anxiety - i.e., BZs have anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant and amnestic (impair short-term memory) properties. While benzodiazepines (BZs) are well appreciated for their ability to alleviate anxiety (i.e., their anxiolytic properties) shortly after administration, they are also known for their ability to promote dependence and are frequently abused. Current recommendations for using BZs to treat anxiety in GAD allow no more than 2-4 weeks of BZ exposure. Antidepressants (e.g., SSRIs / SNRIs) have become a mainstay in treating GAD in adults.

First-line mediations from any drug category often include drugs that have been approved by the Food and Drug Administration (FDA) for treating GAD because these medications have been proven safe and effective for treating GAD.

FDA-approved medications for treating GAD

FDA-approved medications for treating GAD include:

1. SSRIs
   1. Paroxetine
   2. Escitalopram
2. SNRIs
   1. Venlafaxine
   2. Duloxetine
3. Benzodiazepines (BZs)
   1. Alprazolam: Alprazolam is the only FDA-approved BZ for treating GAD.
4. Azapirones
   1. Buspirone
   
   

Non-FDA approved medications

While certain medications are not specifically FDA approved for treatment of GAD, there are a number of medications that historically have been used or studied for treating GAD. Other medications that have been used or evaluated for treating GAD include:

• SSRIs (antidepressants)
  • Citalopram
  • Fluoxetine
  • Sertraline
  • Fluvoxamine (SSRI)
• Benzodiazepines
  • Clonazepam
  • Lorazepam
  • Diazepam
• GABA analogs
  • Pregabalin (atypical anxiolytic, GABA analog)
  • Tigabine
• Second-generation antipsychotics (SGAs)
  • Olanzapine (evidence of effectiveness is merely a trend)
  • Ziprasidone
  • Risperidone
  • Aripiprazole (studied as an adjunctive measure in concert with other treatment)
  • Quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients)
• Antihistamines
  • Hydroxyzine (H1 receptor antagoinst)
• Vilazodone (atypical antidepressant)
• Agomelatine (antidepressant, MT1/2 receptor agonist, 5HT2c antagoinst)
• Clonidine (noted to cause decreased blood pressure and other AEs)
• Guanfacine (a2A receptor agonist, studied in pediatric patients with GAD)
• Mirtazepine (atypical antidepressant having 5HT2A and 5HT2c receptor affinity)
• Vortioxetine (multimodal antidepressant)
• Eszopiclone (non-benzodiazepine hypnotic)
• Tricyclic Antidepressants
  • Amitriptyline
  • Clomipramine
  • Doxepin
  • Imuipramine
  • Trimipramine
  • Desipramine
  • Nortriptyline
  • Protriptyline
• Hydroxazine
• Opipramol (atypical TCA)
• Trazodone
• Monamine Oxidase Inhibitors (MAOIs)
  • Tranylcypromine
  • Phenalzine
• Homeopathic preparations (discussed below, see complementary and alternative medications (CAMs))

Complementary and Alternative Medicine (CAMs) studied for potential in treating GAD

CAMs are widely used by individuals who suffer GAD despite having no evidence or varied evidence regarding efficacy. Efficacy trials for CAM medications often suffer from various types of bias and low quality reporting in regard to safety. Critics point out that CAM trials sometimes predicate claims of efficacy based on a comparison of a CAM against a known drug after which no difference in subjects is found by investigators and which is used to suggest an equivalence between a CAM and a drug. Because this equates a lack of evidence with the positive assertion of efficacy, a "lack of difference" assertion is not a proper claim for efficacy. Moreover, an absence of strict definitions and standards for CAM compounds further burdens the literature regarding CAM efficacy in treating GAD. CAMs studied for their potential in treating GAD include:

1. Kava Kava (Piper methysticum) extracts: Meta analysis does not suggest efficacy of Kava Kava extracts due to few data available yielding inconclusive results or non-statistically significant results. Nearly a quarter (25.8%) of subjects experienced adverse effects (AEs) from Kava Kava extracts during six (6) trials. Kava Kava may cause liver toxicity.
2. Lavender (Lavandula angustifolia) extracts: Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation. Silexan is an oil derivative of Lavender studied in pediatric patients with GAD. Concern exists regarding the question as to whether Silexan may cause unopposed estrogen exposure in boys due to disruption of steroid signaling.
3. Galphimia glauca extracts: While Galphima glauca extracts have been the subject of two (2) RCTs comparing Galphima glauca extracts to lorazepam, efficacy claims are regarded as "highly uncertain."
4. Chamomile (Matricaria chamomilla) extracts: Poor quality trials have trends that may suggest efficacy but further study is needed to establish any claim of efficacy.
5. Crataegus oxycantha and Eschscholtzia californica extracts combined with magnesium: A single12-week trial of Crataegus oxycantha and Eschscholtzia californica compared to placebo has been used to suggest efficacy. However, efficacy claims require confirmation studies. For the minority of subjects who experienced AEs from extracts, most AEs implicated gastrointestinal tract (GIT) intolerance.
6. Echium amoneum extract: A single small trial used this extract as a supplement to fluoxetine (vs using a placebo to supplement fluoxetine); larger studies are needed to substantiate efficacy claims.
7. Gamisoyo-San: Small trials of this herbal mixture compared to placebo have suggested no efficacy of the herbal mixture over placebo but further study is necessary to allow definitive conclusion of a lack of efficacy.
8. Passiflora incarnata extract: Claims of efficacy or benzodiazepam equivalence are regarded as "highly uncertain."
9. Valeriana extract: A single 4-week trial suggests no effect of Valeriana extract on GAD but is regarded as "uninformative" on the topic of efficacy in view of its finding that the benzodiazepine diazepam also had no effect. Further study may be warranted.

Other possible modalities discussed in literature for potential in treating GAD

1. Acupuncture: A single, very small trial revealed a trend toward efficacy but flaws in the trial design suggest uncertainty regarding efficacy.
2. Exercise (as an addition to CBT)
3. Balneotherapy: Data from a single non-blinded study suggested possible efficacy of balneotherapy as compared to paroxetine. However, efficacy claims need confirmation.
4. Therapeutic massage: A single, small, possibly biased study revealed inconclusive results.
5. Resistance and aerobic exercise: When compared to no treatment, a single, small, potentially unrepresentative trial suggested a trend toward GAD remission and reduction of worry.
6. Chinese bloodletting: When added to paroxetine, a single, small, imprecise trial that lacked a sham procedure for comparison suggested efficacy at 4-weeks. However, larger trials are needed to evaluate this technique as compared to a sham procedure.
7. Floating in water: When compared to no treatment, a single, imprecise, non-blinded trial suggested a trend toward efficacy.
8. Swedish massage: When compared to a sham procedure, a single trial showed a trend toward efficacy.
9. Ayurvedic medications: a single non-blinded trial was inconclusive as to whether Ayurvedic medications were effective in treating GAD.
10. Multifaith spiritually-based intervention: a single, small, non-blinded study was inconclusive regarding efficacy.

---

The following is work on the Diagnosis section of the GAD article.

Diagnosis

DSM-5 criteria

Diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders DSM-5 (2013), published by the American Psychiatric Association, are summarized as follows:

1. "Excessive anxiety or worry" experienced most days over at least six (6) month and which involve a plurality of concerns.
2. Inability to manage worry.
3. At least three (3) of the following occur:
   1. Restlessness
   2. Fatigability
   3. Problems concentrating
   4. Irritability
   5. Muscle tension
   6. Difficulty with sleep

   Note that in children, only one (1) of the above items is required.

   
   
4. One experiences significant distress in functioning (e.g., work, school, social life).
5. Symptoms are not due to drug abuse, prescription medication or other medical condition(s).
6. Symptoms do not fit better with another psychiatric condition such as panic disorder.

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders(2004); minor changes include wording of diagnostic criteria.

ICD-10 criteria

The 10th revision of the International Statistical Classification of Disease (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:

1. A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
2. At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).

   Autonomic arousal symptoms

   (1) Palpitations or pounding heart, or accelerated heart rate.

   (2) Sweating.

   (3) Trembling or shaking.

   (4) Dry mouth (not due to medication or dehydration).

   Symptoms concerning chest and abdomen

   (5) Difficulty breathing.

   (6) Feeling of choking.

   (7) Chest pain or discomfort.

   (8) Nausea or abdominal distress (e.g. churning in the stomach).

   Symptoms concerning brain and mind

   (9) Feeling dizzy, unsteady, faint or light-headed.

   (10) Feelings that objects are unreal (derealization), or that one's self is distant or "not really here" (depersonalization).

   (11) Fear of losing control, going crazy, or passing out.

   (12) Fear of dying.

   General symptoms

   (13) Hot flashes or cold chills.

   (14) Numbness or tingling sensations.

   Symptoms of tension

   (15) Muscle tension or aches and pains.

   (16) Restlessness and inability to relax.

   (17) Feeling keyed up, or on edge, or of mental tension.

   (18) A sensation of a lump in the throat or difficulty with swallowing.

   Other non-specific symptoms

   (19) Exaggerated response to minor surprises or being startled.

   (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.

   (21) Persistent irritability.

   (22) Difficulty getting to sleep because of worrying.

3. The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
4. Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.

See ICD-10 F41.1 Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80).

Genetics[edit]

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there an hereditary basis for GAD, but the exact nature of this hereditary basis is not fully appreciated.  While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD.  Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality.  Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors (e.g., life experience or ongoing stress) that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who suffer anxiety disorders, including GAD). Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder (MDD), which may explain the common occurrence of MDD in individuals who suffer GAD. When GAD is considered among all anxiety disorders (e.g., panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30-40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals who suffer GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD (irrespective of other individual characteristics).

Studies of possible genetic contributions to development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g., in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes suggested as having a significant relationship to development of GAD or demonstrated to have had a relationship to treatment response include:

• PACAP (A54G polymorphism): remission after 6 month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013))
• HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of Venlafaxine treatment (Lohoff et al. (2013))
• SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of Venlafaxine treatment (Lohoff et al. (2013))

--

MGH text highlights: amygdala, insula, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC, possibly), and hippocampus.

Pathophysiology drafting:

The pathophysiology of GAD is an active and ongoing area of research often involving the intersection of genetics and neurological structures. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (OFC). It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD. Individuals who GAD have been suggested to have greater amygdala and medial prefrontal cortex (mPFC) activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex (e.g., prefrontal cortex or the orbitofrontal cortex (OFC)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of frontal cortex (e.g., dorsomedial prefrontal cortex (dmPFC)) that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age (e.g., amygdala activation in adolescents with GAD).

This is my best summary of Etkin (working off of the original drafting that referenced Etkin): GAD has been suggested to involve increased connectivity between an executive network linking the frontal and parietal lobes with the amygdala but decreased connectivity between a network linking the insula and cingulate cortex with the amygdala (i.e, the salience network).

- still Etkin is a primary resource . . . so might not use it.