Anxiety Disorders Begin Earlier in Life,
Differ by Gender

Jeff Craven

August 19, 2020

Anxiety disorders start very early in life and may manifest themselves first as other conditions like social anxiety disorder, according to Jeffrey R. Strawn, MD.

An adolescent presenting to a mental health clinician with anxiety at 16 years old, for example, has likely struggled with her anxiety for years before visiting a clinic. "That child may have been someone who had separation anxiety earlier in life and who as, even an infant, had behavioral inhibitions, that reluctance or timidness to explore new things, that tendency to retreat from novel stimuli," Dr. Strawn, associate professor of psychiatry, pediatrics and clinical pharmacology at Cincinnati Children's Hospital Medical Center, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. "Anxiety disorders are enduring and persistent, and they begin very early in life."

Social anxiety disorder is one of the first anxiety disorders that appear in childhood or adolescents, which rises during puberty and during a time in a child's life when they are dealing with new social pressures and challenges, such as graduating from elementary to middle school, Dr. Strawn noted.

Generalized anxiety disorder is usually the next to emerge, followed by panic disorder. On the other hand, agoraphobia, another anxiety disorder that begins in childhood, "often represents behavioral avoidance as opposed to agoraphobia as we classically think about it as adult psychiatrists."

Onset of anxiety disorders also differ by gender. "In terms of the emergence of these anxiety disorders, another thing that's important to know is that the onset seems to be a bit different with regard to girls and boys. We see that break there emerging really around the time of puberty or as people are moving into late puberty, at least for girls," Dr. Strawn said at the meeting presented by Global Academy for Medical Education.

A shift occurs in amygdala prefrontal circuitry as children age, Dr. Strawn explained. Younger children do not have the ability to modulate the amygdala with their prefrontal cortex, but this amygdala–medial prefrontal cortex functional connectivity will change as children grow. A study by Dylan G. Gee, PhD, and colleagues found positive amygdala–medial prefrontal cortex functional connectivity at younger than 10 years old, and a "steady decline in amygdala activity" from 10-13 years to adulthood at 22 years old (J Neurosci. 2013 Mar 6;33[10]:4584-93).

"In essence, what we're seeing is that there's improvement or more effectiveness in terms of that connection between the prefrontal cortex, the amygdala, and that ability to amplify the brake to the amygdala," Dr. Strawn said.

SSRIs, SNRIs for Pediatric Patients

Selective serotonin reuptake inhibitors can be effective for pediatric patients with anxiety disorders. Results from the Child/Adolescent Anxiety Multimodal Study (CAMS) show that patients with generalized separation or social anxiety disorder treated with sertraline or cognitive-behavioral therapy (CBT) for 3 months responded better to treatment than placebo. A combination of sertraline and CBT performing best, compared with either intervention alone (N Engl J Med. 2008;359:2753-66).

When examining treatment response in 76 patients from CAMS, the researchers saw improvement at 4 weeks from baseline in patients with anxiety symptoms receiving CBT, but no significant change in improvement after 4 weeks up to 12 weeks (J Child Adolesc Psychopharm. 2017 Aug 1. doi: 10.1089/cap.2016.0198).

"What that actually means is that your improvement at week 4 is better than your improvement at baseline, and your improvement at week 8 is greater than your improvement at week 4. Similarly, in your improvement, week 12 is greater than your improvement at week 8," Dr. Strawn said.

However, "that's not the case for aggressively titrated sertraline," which had no statistically significant difference in improvement at 8 weeks and 12 weeks, he explained. "What this actually means is that, if I have not had improvement by week 8, there is a three-to-one odds against improvement over those next 4 weeks. The take-home message here is really that an adequate trial for an SSRI in pediatric anxiety disorders is probably about 8 weeks ­— not 12, not longer."

Serotonin norepinephrine reuptake inhibitors (SNRIs) are also effective in pediatric patients with anxiety disorders.

"Both SNRIs as well as SSRIs have certainly demonstrated efficacy in terms of treating pediatric patients with anxiety, but there is a very important difference here with regard to the trajectory of improvement and also the magnitude of improvement," Dr. Strawn said. SNRIs like atomoxetine, duloxetine, or venlafaxine "do not improve as rapidly and do not improve to the same extent as kids who are treated with an SSRI."

Dose is another factor that affects symptom improvement in patients with pediatric anxiety disorders. In a 2018 meta-analysis, Dr. Strawn and colleagues found that patients treated with a higher dose of SSRIs demonstrated more rapid improvement at 2 weeks, compared with patients who received SNRIs (P = .002), but there was no significant difference in overall response trajectory (J Am Acad Child Adolesc Psychiatry. 2018 Apr;57[4]:235-44.E2).

Response to SSRIs can depend a patient's genotype, Dr. Strawn said. The serotonin transporter promotor polymorphism has received "considerable attention in adults with depressive disorders primarily" but also might play a role in anxiety disorder response in pediatric patients.

One study presented by his group at the 2019 annual meeting of the American Academy of Child & Adolescent Psychiatry showed that patients with a short-short copy of the serotonin transporter promoter polymorphism instead of a long copy had "shallower and less improvement over the course of treatment" when taking escitalopram.

"This is something that doesn't necessarily compel us to use an SNRI over an SSRI, but it's something that does give us some important information in terms of the trajectory of improvement," he said.

When it comes to side effects of SNRIs and SSRIs, the profile is "pretty consistent with what we know to be the side effect profile in adults with depressive and anxiety disorders," Dr. Strawn noted. "SNRIs tend to be a little bit better tolerated, both in terms of adverse event–related discontinuation and also in terms of their likelihood of producing activation."

Patient and caregiver expectations can further affect response to treatment. In CAMS, "patients who had a greater expectation that the medicine would actually work tended to have much greater improvement in symptoms," Dr. Strawn said. "I think this has implications in terms of how we actively manage expectations and discussions about the evidence for interventions with our patients in the clinic."

Global Academy and this news organization are owned by the same parent company. Dr. Strawn reported receiving research support from Edgemont Pharmaceuticals, Eli Lilly, Forest Research Laboratories, Lundbeck, the National Institutes of Health, Neuronetics, and Shire. He also reported receiving royalties from Springer Publishing, and is a consultant for and receives material support from Assurex/Genesight.

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