“A tendency to melancholy, let it be observed, is a misfortune, not a fault.”- A. Lincoln
The diagnosis of the mental state of public figures is an overwhelming impulse for some, particularly in the current political season where terms like “narcissism”, “pathological liar”, and “megalomaniac” are now a routine part of the discourse. Such judgments are not limited to the current campaign season – plenty of ink has been devoted to the perceived mental status of our former leaders, most notably our Presidents.
Few Presidents are as universally admired and studied as Abraham Lincoln.
Apart from the tremendous challenges he faced during one of the most difficult periods of our country’s history, Lincoln suffered with what scholars believe was profound depression at a time when treatments were few and ineffective.
Lincoln endured bouts of melancholy for much of his life, and by some accounts it was an essential part of his nature. He was not always depressed, but what may have been a predisposing family history and tragic loss seemed to trigger dark moods and what some have claimed to be suicidal ideation.
The word “Melancholy” (literally, “black bile”), has its roots in the ancient Greek belief that the body possessed four “humors”, which in the right balance produced good health. The notion of “bile” in this context doesn’t relate directly to bile made by the liver. Nevertheless, imbalance in these humours, and in particular too much black bile was thought to cause feelings of depression.
Today we know it doesn’t work that way. But a different imbalance – one of brain chemicals and circuits – is known to disrupt mood when it occurs in particular parts of the brain. The emotional brain includes extended circuits involving the prefrontal cortex, amygdala, hippocampus and brainstem that may respond differently in depressed brains.
In the 1960s, drugs that were known to deplete levels of brain chemicals called monoamines were observed to lead to depressed mood. This observation set the stage for many of the current drug treatments for depression.
These drugs, called antidepressants, may help restore balance in emotional circuits mainly by increasing the levels of neurotransmitters in the synapse. For example, depletion of synaptic serotonin levels has led to the monoamine, or “serotonin hypothesis”, which holds that restoring serotonin levels in the synapse should be restorative to depressed moods. Serotonin is released throughout the brain via projections from a brainstem region called the dorsal.
The most commonly used antidepressants act at special molecules at the synapse that normally transport serotonin back into the terminals from this projection. By blocking or reducing the amount of serotonin transported into the terminal, antidepressants cause more serotonin to linger in the synapse. It makes a tidy story, but it’s only scratching the surface.
The response of the brain to serotonin is complicated, and occurs through at least seven serotonin (abbreviated “5-HT” for 5-hydroxytryptamine) receptors, which may either inhibit or excite brain cells. Only the 5-HT3 receptor appears to directly open the gates to an ion channel – serotonin binds to the six others, and initiates a series of biochemical interactions within the cells. The net effect of these interactions depends on whether the receptor is on the terminal that sends the signal, or on the cell that receives the signal.
Many drugs don’t simply modify activity at synapses – through these cellular cascades, some drugs can actually change the brain at a structural (and therefore functional) level. The signaling pathways evoked by this stimulation include cascades of molecular interactions and the synthesis of new proteins and growth factors. Many of these can act to tweak activity within the brain’s emotion circuits, even promoting growth of new neurons and connections. This plasticity is one of the reasons that assessing whether an antidepressant is effective may take weeks.
The classical pharmacological approach to depression isn’t yet exhausted. There’s a continuing search for treatments that are more effective with fewer side effects. Psilocybin, a hallucinogen that is the active ingredient in magic mushrooms, has been shown to act rapidly in clinical trials – it also increases serotonin levels by acting at 5-HT1A/2A/2C receptors. Psilocybin, in imaging studies, alters the functional connectivity of the brain even as it produces an altered state of consciousness. It is reported to reduce activation of the amygdala (an important emotion processing area) by negative emotional stimuli, and this effect correlates with how well the drug elevates mood after the treatment. An open label study in 12 patients with unipolar depression showed rapid reduction of depressed symptoms at 1 week and 3 months out, including positive relief of anxiety.
Ketamine has also been found to possess potent and fast acting antidepressant effects. Ketamine is a type of glutamate receptor antagonist, acting mainly at the n-methyl-d-aspartate (NMDA) glutamate receptor.
Recent studies suggest that the effect on depression symptoms is not through NMDA receptors, but occurs through metabolites of the drug. If this finding holds (so far it’s only been tried in rodents using rodent behavioral models that are thought to be good surrogates for human depressive behaviors) it’s good news, because it means that the therapeutic benefit of the drug might be separable from the anesthetic effects of the drug, which rely on the classical glutamate receptor blockade. But until there’s a human trial we won’t know for sure.
Why isn’t everyone cured of their depression by antidepressants? The sad truth is it’s not known for sure. It’s estimated 10-30% of patients don’t respond to treatment. But there are two challenges to effective treatment by current approaches that probably account for at least some of the limited efficacy of antidepressants.
The first is that the complexity of the brain itself means that it’s unlikely that the brain’s emotional life can be completely determined by only a chemical or two. The serotonin hypothesis has been a powerful insight into the likely pathways involved in major depression, but expecting that one drug alone will be sufficient to fine tune such a complex network may be asking too much. Add to this each individual’s complexity – the fact of individual genetic differences – and it becomes less likely that even a drug that is effective across the population will always be effective for a particular person’s depression. This is why it is important to not lose hope when only one medication has been tried. The emerging concept of personalized and precision medicine has been deployed in diseases such as cancer, but the concept will also have powerful utility if extended to understanding and promoting good mental health.
The other challenge in depression is that it’s a state that is influenced by the cognitive processes of the affected individual, which may contribute to the initial state of depression and which may resist treatment. Even without modern treatments, Lincoln found a way to live with his melancholy. Perhaps it wasn’t as deep as some have suggested. Or, he was able to cope with the supportive friends and loved ones in his life, his love of a good joke and his driving ambition to live a life of purpose. We know that just as negative self-talk and impaired processing of emotion can contribute to depression, cognitive therapies can help those with depression change how they process negative emotions and can enhance recovery compared to drugs alone.
Could it be that Lincoln’s melancholy made him exactly the President we needed during the Civil War? In an America that was divided against itself, perhaps the nation needed a President who was strengthened by enduring and overcoming the struggles within his own mind.
If you need help now, call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255) or visit their website. Your healthcare provider will also be a good source of treatment and help. A lay guide to depression and its symptoms can be found at the NIMH website.
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