Depression: Mental Illness with Mixed Genetic and Developmental Components

By Frank Amthor

Depression, which affects nearly 15 percent of the population, is the most serious form of mental illness in terms of total cost. Some sources estimate the direct and indirect costs at over $50 billion yearly in the United States alone.

Depression is poorly understood, but the term clearly designates many different syndromes and diseases, some of which may have a strong genetic basis, while others may not. For example, there are many cases in which people have been without any significant depression their entire lives but have been plunged into depression by a single traumatic experience, such as death of a child or spouse. Depression also appears to result from chronic lower-level stress. Depression also develops in some individuals and families with high hereditability in the absence of any identifiable environmental trigger.

Following are some theories about depression and therapies based on them.

Monoamine hypothesis: Not enough serotonin

The monoamine hypothesis suggests that depression results from a deficit in the neurotransmitter serotonin. Most anti-depressants (particularly recent ones like Prozac) are designed to elevate serotonin levels; many also tend to elevate the levels of norepinephrine and dopamine.

However, depressed people do not show abnormally low serotonin levels, and artificially lowering these levels in people without depression doesn’t result in depression. Thus, although elevating serotonin levels with drugs such as SSRIs (selective serotonin reuptake inhibitors, like Prozac) may alleviate depressive symptoms in some people, it’s not at all clear — and in fact unlikely — that doing so creates a normal brain state in these people by restoring an intrinsic serotonin deficiency.

The anterior cingulate cortex: Blame it on the ACC

Brain imaging studies have pointed to the anterior cingulate cortex as a place in the brain whose activation might be responsible for some types of depression, particularly if associated with pain or chronic pain. The ACC is activated by pain, the anticipation of pain, and negative experiences generally. It also exhibits higher activity levels in depressed people than in non-depressed people. Therapies used to address an over-active ACC include the following:

  • Ablation: In some clinical trials, parts of the ACC were ablated (removed) in order to try to relieve intolerable pain in patients who were terminally ill. Many of these patients reported that they could still physically sense pain, but the sensation was no longer distressing, similar to the effects of some analgesics.
  • Deep brain stimulation (DBS): DBS, which partially inactivates the ACC in severely depressed patients, involves permanently inserting a small electrode into a particular brain area and implanting a stimulating electronic box much like a heart pacemaker that passes current pulses through the electrode. Some of these patients experienced immediate relief from pain as soon as the stimulation current was turned on.

The use of DBS for depression was preceded by a much more common use for Parkinson’s disease patients. DBS stimulation of the subthalamic nucleus has produced immediate symptom relief in thousands of such Parkinson’s patients (the subthalamic nucleus is part of the neural circuit in the basal ganglia that also includes the substantia nigra, the brain areas primarily affected by Parkinson’s disease).

Shock treatments, negative feelings or emotions, and memory

Many studies have shown that people tend to interpret experience more negatively when they are depressed. A class of theories that might usefully be termed downward spiral theories suggests a feedback process in which negative feelings or emotions create negative memories, creating further negative feelings or emotion, eventually resulting in inescapable depression.

If this is the way depression works, the therapeutic strategy is to break this feedback cycle. Two types of neuronal-modulation alternatives to pharmacological therapies therapy have been used to this effect: electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).

  • Electroconvulsive therapy (ECT): ECT involves passing electric currents through the brain via scalp electrodes. The purpose is to induce a transient seizure that temporarily interrupts brain activity and causes retrograde memory loss. This memory loss typically spans the previous several months, some of which is recovered over the next days and weeks. There can also be anterograde memory loss, reduced ability to form new long-term memories, for several weeks.

ECT was used frequently during the latter half of the 20th century for cases of intractable depression that involved significant risk of suicide. It was considered relatively non-invasive. However, its use fell out of favor for several reasons: a general dislike of inducing seizures in patients; the fact that there were frequent reports of lasting cognitive deficits including, but not limited to, memory loss; the fact that its effects often lasted only for a few months; and the availability of alternative pharmacological treatments that showed promise in some patients.

  • Transcranial magnetic stimulation (TMS): In the last decade, TMS has been used in a somewhat similar manner to ECT. TMS involves creating a high-field magnetic pulse over a particular brain area via an external coil through which a high current is passed for a number of milliseconds. This magnetic field pulse produces currents inside the brain underneath the coil. Although the neural details of exactly how the electric currents affect the brain are not entirely clear, TMS does shut down brain activity in the affected area transiently without inducing a seizure (although it can produce seizures, especially if the stimulation is bilateral — that is, involving areas of both sides of the brain at the same time).

Some clinicians have claimed success in treating depression with TMS. While the jury is still out because no large, appropriately randomized clinical trials have been done, the technique appears to be much more benign than ECT.

TMS was originally a research tool that was used to answer questions about whether processing in a particular brain area was necessary for perception or motor behavior. For example, researchers presented stimuli requiring subjects to make a judgment about movement while creating TMS pulses over motion detecting areas of visual cortex. When the TMS pulse compromised the subject’s ability to do something, it generally validated brain imaging experiments that showed activity in the same area at a particular time associated with doing the same task.