Depression affects many of us, and in some cases medication is needed. Antidepressant acts on the "balance" in the brains "neurochemistry", but how do they work? And what characterizes a depression? Anyway, depression remains an illness that needs better treatment options. The trend is for newer agents to either be more specific or have a better side effect profile.
To be considered a medically treatable disorder, depression must exceed the short-term ‘blues’ we all feel when our goals are not met or life takes a turn for the worse. The distinguishing features of clinical depression include:
- Symptoms must rise to the level that they interfere with eating, sleeping or daily activities.
- Symptoms must appear daily (or nearly so) for a period of two weeks or more.
- To be primary depression, symptoms must not be due to substance abuse (or withdrawal) or directly attributable to the recent loss of a loved one. (Note, some clinicians will include other major life stressors, such as job loss or medical diagnosis.)
- Primary depression cannot be the result of another medical condition – such as hypothyroidism. A medical history should rule out hormonal causes before treatment of depression begins (including medication history).The modern paradigm for the biology of depression revolves around three neurotransmitters and their actions in the brain. The phrase, ‘chemical imbalance’ is often used to describe the effects of various levels of these neurotransmitters, but it is misleading in that there is no agreed upon ‘balance’ to measure, other than a reduction of symptoms. This is important, because, unlike blood-sugar levels (a single measurable number), it takes a skilled practitioner to evaluate individual patients and drug effects.
- Those suffering depression will report either a depressed mood (profound hopelessness) or an inability to act in the world. This latter isn’t merely unwillingness, it is felt as an uncontrollable physical and mental lassitude and ranges from deep ennui to obvious disengagement. Patients will report they can no longer enjoy those activities which used to bring pleasure.
Serotonin, norepinephrine and dopamine are the three main neurotransmitters targeted by the commonly prescribed antidepressants. While it is known that depression is related to various levels of these neurotransmitters (hence the phrase, chemical imbalance) the relationship is not perfectly clear. As an example, one depressed patient may show lower than normal levels of norepinephrine and respond well to a drug which increases norepinephrine levels. Other patients with depression show a higher than normal level of norepinephrine.
The picture is far from simple and not clear. With 30 neurotransmitters to consider, the brain remains a very complex place to do business. Therapy is based on results – often, several medications must be tried until a ‘match’ is found. And even with the large number of drugs available, approximately 30% of patients will not get chronic relief with medications.
- Tri-cyclic Antidepressants (TCAs) – The first class of medications used primarily to treat depression, these drugs were initially marketed in the late 1950s. The first, Imipramine, is still in use today. They find application in serious or intractable depression, but are limited because of a significant side effects profile, including tremor and cardiac arrhythmia.
TCAs act to increase serotonin and norepinephrine (strong) as well as dopamine (weak). They have an antihistamine effect peripherally and interact strongly with alcohol. In low doses, they are sometimes used as a sleep aid.
- Mono-Amine Oxidase Inhibitors (MAOIs) – These drugs block the action of mono-amine oxidase, the primary enzyme which degrades serotonin, norepinephrine and dopamine (as well as other neurotransmitters). By blocking this enzyme, MAOIs keep naturally occurring neurotransmitters in the synaptic junction longer, leading to a greater effect for however much transmitter is produced.
MAOIs, like TCAs, have a poor side effects profile, which limits their use. The blocking of mono-amine oxidase occurs throughout the body and, because the breakdown of amines is inhibited, a buildup occurs. Foods to be avoided contain tryptamine and tyramine. There are also a large number of other drugs which are metabolized by amine oxidation and patients on MAOIs must be screened for interactions.
- Selective Serotonin Reuptake Inhibitors (SSRIs) – This newer class of compounds acts to keep available serotonin in the synaptic junction by slowing its reabsorbtion back into the neuron. This is the second of two removal mechanisms for serotonin. The first, degradation is blocked by MAOIs. Unlike MAOIs and TCAs, SSRIs tend to primarily affect serotonin levels (although specificity varies with different drugs).
In comparison to MAOIs and TCAs, this class has very few side effects that rise to the level of having to discontinue the medication. This makes them first line agents for depression and even non-specialists may feel comfortable prescribing them. An even newer class, serotonin-norepinephrine reuptake inhibitors (NSRIs) is also used in depression.
One cautionary note: Because agents in different classes have different modes of action with the same result (increased synaptic neurotransmitters) a washout period is required when switching medications. Consider what would happen if a patient were on an MAO along with an SSRI. The neurotransmitter, serotonin would be blocked from degradation (the MAOI) and reabsorbtion (SSRI). This can lead to supra-additive effects. Consequently, patients have to be weaned from one before starting the other. This can mean a period of essentially no benefit and patients are likely to relapse until the second agent begins to take effect.
Atypical and Treatment Resistant Depression
The agents mentioned above are all considered traditional antidepressants and most patients (in the US) receive them through their primary care physician (60+%). Atypical depression and resistant depression (two to four agents have failed) usually require the services of a psychiatrist or psychologist trained in these more intractable cases.
Often, medications will then be tried that are not classically thought of as antidepressants (benzodiazepines or antipsychotics). Atypical depression, for instance, may respond to lithium. Beyond this, treatment options extend from talk therapy sessions all the way through electroconvulsive therapy (shock therapy).
Depression remains an illness that needs better treatment options. Medications are still a good area of research as are transcranial magnetic stimulation and magnetic seizure therapy. Reducing adverse reactions is also an important consideration because patients will likely take medication for months or years. The trend is for newer agents to either be more specific or have a better side effect profile.