Zac LaRocca-Stravalle, Biology Major, Class of 2021
This is a position paper regarding the use of antidepressant for adolescence. This paper claims that the use of antidepressants for adolescents with depressive symptoms ought to be considered, but with careful evaluation. The reason I decided to research this topic is because depression is becoming a big issue in the world, particularly in the US, and those affected by depression include adolescents. I was curious about the effects that antidepressant use had on adolescents, considering that it is a time of critical brain development.
Antidepressants in Adolescents: How it is Beneficial and Why We Should be Wary
Depression is a global health concern and is considered one of the leading causes of mental disability worldwide, which is expected to rise. Depressive symptoms are most prevalent in the adolescent and young adult population, as are the risk for many other affective disorders, such as anxiety disorders. Among adolescents with depression, moderate to severe depression account for one third of all depressive symptoms. In the United States, where rates of depression are the highest of any other developed nation, 2.8 million adolescents aged 12-17 presented major depression in 2014, around 11% in that age group (Center for Behavioral Health Statistics and Quality, 2015). Major depression is a risk factor for suicidality, and associated with social and academic impairments, anxiety disorders, substance abuse and physical health problems. About 20% of adolescents with moderate to severe depression show recurrent depressive symptoms throughout life, and it is most prevalent in those with major depression (Rushtonm, et al., 2002).
Although adolescents that develop moderate or severe depression are at risk for recurrent depressive episodes later in life, there is little research that characterizes the course of depression from adolescence to adulthood with regard to the development of recurrent and chronic depression. This is key to understanding the extent that antidepressants affect the development of adolescent depression, let alone ameliorate depressive symptoms. This essay evaluates the role of antidepressants, with particular focus on selective serotonin reuptake inhibitors (SSRIs), in the context of adolescent development, with the argument that the use of antidepressants for adolescents with depressive symptoms is indicated, but not without careful evaluation.
Adolescence is a time of great neurodevelopment. Cortical grey matter volume peaks at around 12 years, taking an inverted U-shape, and white matter follows a linear increase across ages 4 to 20 (Lenroot & Giedd, 2006; Giedd, et al., 1999). Maturation of many brain structures also occur through adolescent years. In combination with these structural and connectivity developments, neurotransmitter pathways also change. The dopamine pathway, for example, has been shown to change substantially, with dopamine levels peaking in adolescence. The increase in dopamine parallels the increases in dopamine receptor dendrites, innervation density and axonal length (Cousins & Goodyer, 2015). Serotonin pathways, too, are important in adolescent development and facilitate synaptic growth in childhood. These changes in neurotransmitter pathways play a central role in heightened reward sensitivity seen throughout adolescence, and are associated with changes in adolescent behavior, such as risk taking and mood alterations.
Despite this overall development, there is evidence that neurodevelopment is altered in adolescents with affective disorders. The differences between adolescents with and without depressive symptoms is important in the functioning of antidepressants. Those with depression generally have decreased brain volume compared to controls, and adolescents aged 12 to 16 at high risk of depression have reduced hippocampal and putamen growth, as well as a sex differential in amygdalar volume (Whittle, et al., 2014). As a comorbid condition with anxiety disorders, depression is associated with HPA dysregulation. Reasonably, these findings suggest that adolescents with depression, or an onset of depression, have altered neurodevelopment, but it remains difficult to distinguish the effects depression alone has on this development. Evidence suggests that the onset of depression itself is due to childhood conditions and maltreatment. In the extreme cases where there is emotional and physical abuse or neglect in early childhood, the onset of depressive symptoms occurs earlier, develops more severely, and reoccurs more often into adulthood (Cousins & Goodyer, 2015).
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| Fig 1. Group-by-Time Interaction of Selected Brain Volumes in Participants in a Longitudinal Study of Brain Development and Depression Onset During Adolescence(Whittle, et al., 2014) |
The understanding of adolescent brain development is important for evaluating treatments for depression. The use of antidepressants for adolescents have been of particular concern because of the potential vulnerabilities in adolescent neurocognitive development. Antidepressants themselves are known to alter brain function, and providing such medicine to a maturing brain raises concerns. The exact targets of antidepressants, particularly SSRIs, is not fully known, but extensive evidence has shown that SSRIs reactivate hippocampal neurogenesis that is substantially reduced in major depressed individuals (Boldrini, et al., 2012). SSRIs have also been shown to reduce the abrogated connections between the hippocampus and dorsal medial PFC -- strong connectivity between these regions are present in those with depression. SSRIs affect more than just the hippocampus, however. As mentioned, the amygdala is also implicated in depressive symptoms, and clinical studies have shown that SSRIs reduce amygdala response to negative bias in facial expressions (Harmer, et al., 2004).
The extent that SSRIs affect the adolescent brain is still under investigation. Studies focusing on the effects of SSRIs in adolescents have used animal models, and there is evidence for age-dependent effects. One concern in providing SSRIs to adolescents has to do with the interaction between increased serotonin levels and hippocampal development in juvenile and adolescent rats. The increase in serotonin reuptake by fluoxetine has been shown to reduced dendritic branching in the hippocampus, as well as alter protein expression in various hippocampal regions compared to adult rats with the same treatment (Norrholm & Ouimet, 2000). The chronic treatment of fluoxetine in juvenile and early adolescent rats increases serotonin transporter affinity into adulthood. This was not shown when the drug was given to rats later in adolescence and early adulthood. These findings suggest that SSRIs may affect neurodevelopment in adolescence when compared with their adult counterparts. However, there is little clinical research of antidepressant effects on adolescent brain development, and many animal studies used healthy, not depressed, subjects. The evidence that SSRIs exert age-related effects is nonetheless important in addressing possible acute and chronic detrimental effects in neurodevelopment.
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| https://www.psychiatrictimes.com/ssri-prescribing-rates-and-a dolescent-suicide-black-box-hurting-or-helping/page/0/1 |
In 2004, the efficacy of SSRIs came under scrutiny by the US Food and Drug Administration (FDA) in response to research that suggested antidepressant drugs increased suicidality twofold in children. The FDA issued a black box warning and required antidepressant drug manufacturers to include warning labels on their product about the possible link between suicidal behavior in youth and antidepressant use (Singh, et al., 2009). Around the same time, a warning was issued in the United Kingdom for similar concerns. In both instances, the prescription of antidepressants for children rapidly decreased, with some studies indicating a 20% decrease in antidepressant prescriptions for children and adolescents. This reduction in antidepressant prescription, however, was associated with concurrent increases in suicides and sucide attempts in the same age group. Since 1997, when the Center for Disease Control and Prevention (CDC) started documenting suicidality in the US, 2004 marked the highest year-to-year change in suicide attempt rates. Whether or not the lack of antidepressant prescription after the FDA’s warning triggered increased suicidality is not concrete. However, there are similar examples in other countries, such as the Netherlands, where there was a 49% increase in youth suicides during a 22% decrease in SSRI prescriptions in children and adolescents between 2003 and 2005. Even so, no evidence was purported for this sucide-prescription link in the United Kingdom. Taken together, the concerns raised by the FDA and other health organizations may not have warranted statewide alarm, but use of antidepressants for children and adolescents should nonetheless be taken seriously and cautiously. As it stands now, however, opinions are divided.
In contrast to the warnings against the use of SSRIs in children in adolescence, there is clinical evidence that suggest antidepressants have beneficial outcomes in adolescents. Such studies showed that chronic administration of fluoxetine had significant symptomatic remission in youth with moderate to severe depression, and that the use of SSRIs has greater benefit then alternative therapies alone (March, et al., 2005; Goodyer, et al., 2007). In these studies, adolescent participants were divided into four different treatment groups: an antidepressant group, a placebo group, a cognitive-behavioral therapy (CBT) group, and an antidepressant group with CBT. Outcomes were measured byway of depression rating scores and questionnaires. The results in both studies suggested that those given fluoxetine, with or without CBT, improved the greatest, but the effectiveness of antidepressants alone compared to antidepressants with CBT were mixed. Suicidal ideation was reduced in all treatments in both studies and was shown to reduce the greatest in those treated with antidepressants.
The use of antidepressants to treat adolescents with depressive symptoms is warranted, overall. However, it is obvious that the effects of antidepressants on children and adolescents is different from that of adults. Given that adolescence is a time of great neurodevelopment, it is appropriate to be wary of the neurological consequences of antidepressant use, both acutely and chronically. More longitudinal studies of antidepressants on adolescence is needed. As it stands, however, there is no major evidence that precludes the use of antidepressants for human adolescents, despite some of the concerns raised by animal studies. The positive outcomes of antidepressant use in adolescents adds to its efficacy, which may outweigh the benefits of CBT. Therefore, the use of antidepressants for adolescents with depressive symptoms ought to be indicated, but there must be careful evaluation where further research is needed.
References
- Center for Behavioral Health Statistics and Quality, S, 2015. Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health. (HHS Publication No. SMA 15-4927, NSDUH Series H-50).
