Considerable evidence exists that something is askew with the chemistry of the brains of depressives. In order to appreciate that, it is necessary to understand a little about how brain cells communicate with one another. The basic structural and functional unit of the nervous system is the nerve cell or neuron, which is the principal type of brain cell. The neurons are similar to other cells in the body except for two projections—antenna like structures called dendrites for receiving signals and a long projection for transmitting signals called axon.
An axon is capable of transmitting a pulse of electricity (nerve impulse) from the neuron body to some distant target in the brain or the periphery. However, two neurons do not communicate with electrical signals. In fact, there is a small gap between the end of the axon of one neuron and the dendrite of the next neuron (the scientific term for this gap is synapse). The electrical impulse does not cross this gap, but rather causes a chemical (neurotransmitter) to be released from the axon terminals. The neurotransmitter diffuses across the gap and causes electrical changes to occur in the second cell.
Say, a neuron has become excited with some thought or memory (metaphorically speaking); the excitement is an electrical signal—a wave of electricity sweeps from the dendrites over the neuron body, down the axon to the axon terminals. When the wave of electrical excitation reaches the axon terminal, it releases chemical messengers across the synapse. These messengers called ‘neurotransmitters’ bind to specialized receptors on the adjacent dendrite causing the second neuron to be electrically excited.
A small but important piece of housekeeping—what happens to the neurotransmitter after it has done its job and floats off the receptor? In some cases it is recycled—that is taken up by the axon of the first neuron and repackaged for future use. Alternatively, it can be degraded in the synapse and the debris flushed out to the cerebrospinal fluid, then to the blood and the urine.
If these processes fail—either the reuptake by the axon or the degradation in the synapse, then suddenly a lot more neurotransmitter remains in the synapse giving a stronger signal to the second neuron. The proper disposal of the neurotransmitter is a critical piece of neuronal communication.
There are billions of synapses in the brain but only a few hundred neurotransmitters. The same neurotransmitters convey different messages in different parts of the brain. Say, at one synapse, neurotransmitter A sends a message relevant to pancreatic regulation while at another synapse the same neurotransmitter may pertain to emotion.
The best neurochemical evidence suggests that depression involves abnormal levels of one or both of a pair of neurotransmitters—norepinephrine and serotonin. Most of the drugs that lessen depression increase the amount of signalling by these neurotransmitters. One class of anti-depressant called tricyclics, stops the recycling or reuptake of norepinephrine and serotonin in the axon terminals. The result is that the neurotransmitters remain in the synapse longer and is likely to bind to the receptors a second or third time.
A second class of drugs called MAO inhibitors, blocks the degradation of norepinephrine and serotonin in the synapse by inhibiting the action of a crucial enzyme in the degradation, monoamine oxidase (MAO). The result is that more of the messengers remain in the synapses. These findings generate a pretty straightforward conclusion—if you use a drug that increases the amount of norepinephrine and serotonin in the synapses throughout the brain, and as a result someone’s depression gets better, there must have been too little of those neurotransmitters in the first place. Is the case closed?
Naturally, anything connected with the brain is not that simple. As a first issue of confusion, is the problem in depression too little of serotonin or norepinephrine or both? As the tricyclics and MAO inhibitors work on both, it is impossible to say. A class of drugs called SSRI (selective serotonin reuptake inhibitors) work only on serotonin synapses and they work for a large number of patients. A newer class of drugs targets either or both the neurotransmitters depending on drug dosage and have also proven to be very effective.
Another question is whether the real problem is too little of the neurotransmitter in the first place? The stumbling block has to do with timing. In a laboratory, expose the brain to tricyclics and signalling in the synapses changes within hours. However, give that same drug to a depressed person, and it takes weeks for the person to feel better.