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The Neurobiology of Antidepressants.


The nurse requires a thorough understanding of the underlying sciences that directly influence intervention; this is never more important than in the prescribing and administration of drugs. Knowledge of drug activity in the tissues (pharmacodynamics) and the way drugs pass through the body (pharmacokinetics) is essential for appropriate drug administration and the recognition of adverse effects. With the complexity of the nervous system and its disorders, understanding the functions of the neuro-active drugs is never easy. This article describes the known activity of the antidepressant drugs seen in clinical practice, providing insight for the nurse practitioners who deliver, monitor, and control antidepressant chemotherapy.

Neurotransmitters and Depression

The biological activity of the earlier antidepressant drugs gave rise to the concept that depression was due to low levels of serotonin and noradrenaline in the brain. By increasing these levels, depressive symptoms could be relieved. The introduction of antidepressant drugs that do not directly raise the levels of these neurotransmitters has led to a reinterpretation of this concept. It appears that mood can be elevated by drugs that adjust the sensitivity of serotonin and noradrenaline receptors, or regulate movement of these chemicals across synaptic membranes.

The idea that depression was due to a reduction in the level of the brain neurotransmitter serotonin (also known as 5-hydroxytryptamine, or 5-HT) was suggested by observations on two groups of patients. One group was those taking the drug reserpine in the 1960s for high blood pressure, which resulted in a lowering of mood in some. The other group were those taking the antituberculous drug para-amino salicylic acid (PAS), which lifted the mood.[1] It was later found that reserpine blocked the preparation and release of serotonin at neuronal synapses, depleting the amount within the synaptic cleft.[1] Contrary to this, PAS blocked the enzyme monoamine oxidase that destroyed serotonin after use, thus causing the amount of neurotransmitter in the synapse to increase (Fig 1). It is now known that exceptionally low serotonin in the synaptic clefts within the brain is linked with suicide attempts.[3] The serotonin pathways are centered on the nine raphe nuclei of the brainstem. From here neuronal pathways pass to multiple centers of the cerebrum, the limbic area and the basal ganglia.[1,7] These centers are important in the control of mood (the limbic area), the pattern of behavior (the cerebrum), and the management of the sleep-wake cycle (with other areas).[7] Depression not only causes a flattening of affect or mood but behavioral and sleep pattern disturbances as well. The serotonin connection to depression is further supported by studies of serotonin receptors, where a decrease in the number of serotonin receptors has been reported in depressed patients, later becoming normalized by antidepressant therapy.[8]

Noradrenaline is also implicated in depression.[3] Pathways using this neurotransmitter are centered on the locus ceruleus,[1,7] within the pons of the brainstem. From here, pathways pass to the limbic area, hypothalamus and thalamus, cerebellum, and specialized centers within the brainstem.[1] In particular, a reduction in the sensitivity to noradrenaline of specific [Beta]-adrenergic noradrenaline receptors is now considered to be part of the cause of lowered mood. Also, some [[Alpha].sub.2]-adrenergic receptors that exist on the presynaptic membrane of both serotonergic (i.e., those responding to serotonin) and adrenergic (i.e., those responding to noradrenaline) pathways appear to be involved. Activation of these receptors within the adrenergic pathways reduces the amount of noradrenaline released.[3] Within the serotonergic pathways, these receptors normally allow noradrenaline to have some control over the release of serotonin, a system disturbed in depression. It would appear that the two systems, serotonergic and adrenergic, emerging as they do from brainstem origins and passing out to a diffuse area of the brain, are closely integrated in the modulation of mood and therefore the cause of depressive symptoms. Collectively they are often called the diffuse modulatory systems.[1]

The role of a third neurotransmitter in depression, dopamine, is less well established. It has been suggested that possibly the mesocorticolimbic dopamine pathway is at fault in depression, or that the activity of the [D.sub.1] (dopamine) receptor is reduced.[3] The mesocorticolimbic pathway, from the midbrain to the frontal cortex and parts of the limbic system, has a preservation role protecting the individual (e.g., part of both mood and emotional responses) and protecting the species (e.g., involved in reproductive behavior). The role of the [D.sub.1] (dopamine) receptor is less well understood than the [D.sub.2] receptor, but there appears to be a functional relationship between the two receptors related to behavioral patterns of movement.[5]

Pharmacokinetics and Pharmacodynamics

The antidepressants, mood lifting drugs, fall into three main groups: the tricyclics, the "atypical" (or second generation) group, and the monoamine oxidase inhibitors (MAOI). Rapid absorption of antidepressants follows oral administration, with transportation in the blood facilitated by binding to plasma proteins. Initial passage through the liver produces active metabolites from the tricyclic and atypical drugs, and inactive metabolites from the MAOI drugs ("first-pass metabolism"). Most body tissues are ultimately recipients of the drug and its active metabolites when unbound from the blood proteins. Further liver metabolism reduces the effective dosage as the drug and its metabolites are converted into the excretable products. For the tricyclic drugs, which are strongly fat soluble, this liver process involves increasing the water solubility of the drug to allow the metabolites to be excreted in urine.[2]

The tricyclic drugs, including amitriptyline, doxepin, imiprimine, and nortriptyline (Table 1), act by blocking the reuptake of serotonin and noradrenaline into the presynaptic bulb of their respective axons. This action increases the quantity of serotonin and noradrenaline within the synapse,[2] and has previously been seen as the mechanism of mood elevation. However, a time interval of about 3 weeks occurs between the onset of drug treatment and the lifting of depression. This delay is surprising because the drugs act quickly to elevate the neurotransmitter levels, yet the lifting of mood does not follow so soon. Raising the amount of these neurotransmitters at the synapse alone was not enough to improve the mood. In fact, it appears that energy levels are elevated before mood, resulting in a more active yet still depressed patient, a dangerous combination that increases the risk of suicide. Some of these drugs blocked the reuptake of both serotonin and noradrenaline approximately equally (e.g., amitriptyline).[5] The introduction of tricyclic drugs, which selectively block the reuptake of either serotonin (the serotonin selective reuptake inhibitors, [SSRI]) or noradrenaline to a greater or lesser degree, now allows greater flexibility in the choice of drug used. SSRI drugs include fluoxetine, fluvoxamine, citalopram, sertraline, trazodone, and paroxetine. The agent in clinical use that is more selective toward blocking noradrenaline reuptake is maprotiline; whilst others not yet available include oxaprotaline, viloxazine, and nomifensine.[5] Citalopram has nearly 10,000 times more affinity for blocking serotonin reuptake than amitriptyline; whilst oxaprotaline has a similar affinity more than amitriptyline for blocking noradrenaline.[5] Sertraline and trazodone only inhibit serotonin reuptake. A new report suggests that the drug fluoxetine may stimulate the process of neurogenesis (i.e., the formation of new neurones) causing relief of depression, which suggests neuronal losses are a possible cause of the symptoms.[6] Neurons were thought not to regenerate when lost, but stimulation of specific serotonin receptors appears to increase neurogenesis. In this case, many antidepressants may relieve symptoms by increasing serotonin levels, which in turn promotes neurogenesis. The delay in the recovery from symptoms may be due to the time it takes for the new neurons to mature and form their synaptic connections.[6] If these findings are proven then the notion of absent neurogenesis in brain cells will be buried.
Table 1. Selected Antidepressants in Clinical Use

Generic Name Brand Names (UK and USA) Type

Amitriptyline Elavil, Emitrip, Endep Tricyclic
 (all USA) Tryptizol (UK)

Bupropion Wellbutrin (USA) Atypical

Citalopram Cipramil (UK) SSRI

Desipramine Norpramin (USA) Tricyclic
 Pertofrane (USA)

Doxepin Adapin (USA) Sinequan Tricyclic

Fluoxetine Prozac (UK/USA) SSRI

Fluvoxamine Faverin (UK) Luvox (USA) SSRI

Imiprimine Tofranil (UK/USA) Tricyclic

Isocarboxazid Isocarboxazid (UK) MAOI
 Marplan (USA)

Maprotiline Ludiomil (USA) Noradrenaline
 reuptake inhibitor

Mirtazapine Remeron (USA) Zispin (UK) Atypical

Moclobemide Manerix (UK) Reversible MAO-A
 inhibitor (RIMA)

Nephazodone Serzone (USA) Atypical
 Dutonin (UK)

Nortriptyline Allegron (UK) Tricyclic
 Pamelor (USA)

Paroxetine Seroxat (UK) Paxil (USA) SSRI

Phenelzine Nardil (UK/USA) MAOI

Protriptyline Concordin (UK) Tricyclic
 Vivactil (USA)

Sertraline Zoloft (USA) Lustral (UK) SSRI

Tranylcypromine Parnate (UK/USA) MAOI

Trazodone Desyrel (USA) SSRI
 Molipaxin (UK)

Trimipramine Surmontil (UK/USA) Tricyclic

Venlafaxine Efexor (UK) Effexor (USA) Atypical

Viloxazine Vivalan (UK) Noradrenaline
 reuptake inhibitor

Note: Doses not included as they may vary from country to country and by individual patients.

Key: UK (United Kingdom); USA (United States of America); SSRI (selective serotonin reuptake inhibitor); MAOI (monoamine oxidase inhibitor)

The atypical (second generation) antidepressants were originally derived from the tricyclic drugs in an attempt to elevate the mood faster and reduce the tricyclic side effects. They appear to work by readjusting the transportation of serotonin and noradrenaline across the presynaptic membrane and by balancing the postsynaptic receptor sensitivity to the neurotransmitter. By not actually blocking reuptake of neurotransmitter, some of these drugs have significantly reduced the side effects. It is possible that all antidepressants cause an elevation of mood by the same adjustments to receptor sensitivity as the atypical drugs, but take longer to do so. The atypical drugs include several not yet in clinical use, such as iprindole, which increases serotonin receptor sensitivity but reduces the noradrenaline [Beta]-adrenoceptor sensitivity and mianserine, which has the same response as iprindole, but it blocks the presynaptic [[Alpha].sub.2]-adrenoceptors which in turn increases noradrenaline release. Others already in use include bupropion, which has a weak, inhibitory effect on. both serotonin and noradrenaline reuptake and reduces the effects of noradrenaline on adrenergic receptors.

Monoamine oxidase (MAO) is an enzyme that reduces neurotransmitters to their metabolites for excretion, thus providing an essential component of the normal cycle of transmitter production and excretion. Monoamine oxidase inhibitor (MAOI) drugs block these enzymes that are found on the surface of mitochondria within the presynaptic bulb. This allows the accumulation of neurotransmitter within the synapse, mostly serotonin and noradrenaline, but less so dopamine. Their antidepressant effects are probably due to a longer term effect of reducing [Beta]-adrenergic receptor activity whilst increasing serotonin activity, and therefore readjusting the balance between the two neurotransmitters. At least two forms of MAO exist, MAO-A and MAO-B, with the human brain containing mostly MAO-B.[5] Both types metabolize all three neurotransmitters when the concentration of neurotransmitter is low, but become specific at greater concentrations. Also, both types of the enzyme exist in many body tissues, including the liver and the wall of the ileum where they metabolize monoamines in the diet. The oral ingestion of MAOI blocks the activity of the gut wall and liver enzymes and this allows monoamines (particularly tyromine) present in the diet to pass into the blood unaltered (i.e., without oxidation); this could cause a hypertensive crisis. Prescribing MAOI drugs must be accompanied by dietary restrictions of foods rich in monoamines, such as cheese, meat extracts, and red wine, to prevent this complication. These restrictions are not easily achieved in patients who are deeply depressed. The original drugs were irreversible, that is, binding to the enzyme and rendering it permanently inactive, and thus having a long-term effect. These drugs include phenelzine, isocarboxazid, and tranylcypromine.[4] Newer reversible drugs can reduce this complication of food monoamines significantly. They work by binding to the enzyme and making it inactive in an environment where monoamine levels are quite low, allowing this level to build up. However, in an environment of higher concentration of monoamine, the drugs release the enzyme that can then act on the monoamine again. This means that a sudden intake of monoamines in the diet will trigger a reactivation of gut wall and liver enzymes to counteract this rise in concentration, whilst brain enzymes remain blocked where the monoamine level is still low. These reversible drugs also are specific to one of the MAO types. For example, moclobemide is a reversible MAOA-specific drug in clinical practice in the UK, whilst brofaromine, cimoxatone, and toloxatone are similar drugs not yet used clinically. Reversible MAO-B specific drugs are under development and include the new, unused drug caroxazone.


Raising neurotransmitter levels is only one means by which antidepressants act. The activity of modern drugs appears to readjust the balance between serotonin and noradrenaline by more fundamental means. Likely mechanisms include correction of the diminished sensitivity and numbers of specific serotonin and noradrenaline receptors found in depression. Also responsible may be changes in the normal pattern of movements of these transmitters across the synaptic membranes within the diffuse modulatory systems. It is possible that by increasing the serotonin levels these drugs may increase neurogenesis, suggesting that neuronal losses may be a fundamental cause of the symptoms.


I would like to thank Janet Vickers, Maria Dingle, and Lynda Filer of the Division of Applied Biological Sciences of St. Bartholomew School, City University, for their comments on this paper Also my gratitude goes to Shelley Welsman and Rachel Beadle of St. Bartholomew School, City University Audio Visual Aids Department, for their assistance with the diagram.


[1.] Bear MF, Connors BW, Paradiso MA: Neuroscience, Exploring the Brain. Williams and Wilkins, 1996.

[2.] Bradley PB: Introduction to Neuropharmacology. Wright, 1989.

[3.] Kaplan HI, Saddock BJ: Concise Textbook of Clinical Psychiatry. Williams and Wilkins, 1996.

[4.] Karch AM: Lippincott's Nursing Drug Guide. Lippincott Publishers, 1998.

[5.] Leonard BE: Fundamentals of Psychopharmacology. John Wiley and Sons, 1994.

[6.] Motluk A: The more the merrier. New Scientist 1999; 164 (2211): 6.

[7.] Strange PG: Brain Biochemistry a nd Brain Disorders. Oxford University Press, 1992.

[8.] Webster RA, Jordan CC: Neurotransmitters, Drugs and Disease Blackwell Scientific Publications, 1989.

Questions or comments about this article may be directed to: William T. Blows, PhD BSc (hons) RMN RGN RNT OStJ, St. Bartholomew School of Nursing and Midwifery, City University, 20 Bartholomew Close, London EC1A 7QN, England. He is a lecturer in the Division of Applied Biological Sciences.

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Author:Blows, William T.
Publication:Journal of Neuroscience Nursing
Date:Jun 1, 2000
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