Trazodone was discovered in the Seventies by the Angelini research laboratories, and to this day remains a therapeutic option even today in the treatment of depressive disorders both with or without anxiety. In Italy, this drug is fully reimbursed by the National Health System and is available in tablets, drops and injectable solution. Trazodone was patented and marketed in many countries all over the world and became the market leader in the United States during the Eighties. Although the trazodone molecule is about 40 years old, it is still being developed further; in fact, some recent developments aimed at understanding the key role played by brain serotonin result from studies on trazodone or one of its metabolites, i.e. a substance resulting from trazodone breakdown by enzymes present in the human body, called “m-chlorophenylpiperazine”. With time, the study of trazodone has paved the way to further research in order to better characterize the drug’s mechanism of action.

Depression and the Brain

Depression is a real disease; and, although its causes have not yet been entirely elucidated, a link between the onset of this disease and a change in serotonin activity has been clearly identified. Therefore, depression is not a symptom of “weak personality”: it is a serious disease affecting people of every age, ethnicity and level of education. Of the most common chronic conditions in primary care medicine, depression is second only to hypertension. In fact, one patient in ten, among patients of primary-care practitioners, is affected by depression.
To understand some of the reasons leading to the development of this disease, it is necessary to consider how brain cells work.

Brain cells (neurons) actively communicate with each other: information is exchanged through electric signals. For this reason, brain cells have a characteristic structure: a central section, called the “cell body”, which gives rise to a long fibre called the “axon” that transmits the electric message generated within the neuron to another neuron. This latter receives the message through treelike extensions, called “dendrites”, that in turn are connected to the branches originating from the axon of the first neuron through contact points called “synapses”. When a message leaves a neuron, it reaches synapses that are connected to the adjacent neuron and induces both the release and action of chemical substances responsible for transporting this message to the next neuron. These chemical substances, acting as “messengers”, are called “neurotransmitters” because they make sure that the electric message is sent from one neuron to the next.

One of these chemical substances is serotonin. There are also other neurotransmitters, like norepinephrine, dopamine, acetylcholine, histamine, glycine and GABA (gamma-aminobutyric acid). Neurons using serotonin make up the serotonergic system, whereas neurons using norepinephrine are called “noradrenergic neurons”, and so forth.

When a message reaches synapses, from this site neurotransmitters - including serotonin - move to a number of specific points, called “receptors”, located in the adjacent neuron, to complete the message transmission. After this event involving the neuromediator used to transmit the message, a series of events may happen that can stop the delivery of the message to the receiving neuron:
  • The neurotransmitter is released too far from the synapse and is absorbed by other nervous-system cells other than neurons (glyal cells);
  • The neurotransmitter may be attacked and destroyed by special enzymes, like MonoAmino-Oxidase (MAO) for serotonin, norepinephrine and dopamine;
  • The neurotransmitter may be called back to the starting point of the synapse (re-uptake).


How Trazodone Works

Although trazodone’s mechanism of action is not yet entirely clear, it is known that both trazodone and its metabolite m-chlorophenylpiperazine act on signal-sending neurons and on receptors located on the message-receiving neuron.

The action of trazodone on the synapses of the message-sending neuron prevents neurotransmitter re-uptake, especially of serotonin. In this way, it facilitates the delivery of the message to the destination receptor. This partly explains why trazodone is effective in the treatment of depression.

The action of receptors located along the receiving neuron is another of the drug-induced effects, including side effects. In fact, when trazodone binds to special types of such receptors, this agent prevents the neurotransmitter - serotonin - from delivering the message to the receiving neuron. With trazodone, the resulting pharmacological activity is mostly sedative, and this side effect can be a benefit for patients, especially if they also suffer from sleeplessness.



Sleeplessness for more than four weeks is regarded as chronic sleeplessness and requires a close evaluation because this complaint affects the patient’s quality of life and because it is a clear risk factor for the development of depression.

The approach to sleeplessness can be both non-pharmacological and pharmacological treatment. Trazodone and other serotonin-specific antidepressants offer the benefit of alleviating sleep disorders, with a smaller incidence of side effects than other classes of drugs.