The term “depression” is commonly used but is clinically reserved for those people who suffer from a prolonged “low” in their outlook both in terms of their individual day-to-day activities and with their interaction with other people. These lows differ from normal “ups and downs” seen in most individuals at some point in their lives in terms of their severity and duration.
It is estimated that approximately 1 in 10 people suffer from clinical depression at some point in their life. However, the finding that the symptoms and severity of depression varies with each patient complicates the clinical diagnosis. In most cases there is no specific or definable cause that generates the period of depression and the extent of depression may exceed that normally seen following a typical trigger event (e.g. loss of job, bereavement or relationship break-up). Patients suffering from depression often complain of periods of intense sadness, loss of appetite, sleep problems and a sense of personal worthlessness, which is often manifested in withdrawing from friends and family. In extreme circumstances these feelings are so intense that they prompt the sufferer to consider or commit suicide.
Before treatment can begin it is important to assess the extent and severity of an individual’s depression. This means that each patient must be treated as a unique case and the subsequent therapeutic approach tailored to meet that individual’s specific requirements.
Currently, there are two main guides to diagnosis available that are designed to assess and evaluate an individual patient’s depressive state. The International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental disorders, fourth edition (DSM-IV), detail symptoms typically seen in depressed patients. They not only provide an initial assessment of the extent to which each of these symptoms appear in a patient, but also provide a means for starting appropriate treatment strategies for the depressed individual.
Despite the advances in medicine and rigorous scientific investigation into the area of depression, there does not seem to be one unique characteristic that distinguishes a depressed brain from one that is deemed “normal”. Various theories have been put forward which will be discussed briefly, but it would appear that as the brain is a complex organ so too is the underlying physiology and neurochemistry of depression.
Monoamine theory of depression
The monoamine theory of depression involves the hypothesis that a reduced level of important “feel good” chemicals (monoamines such as serotonin, noradrenaline and dopamine) occurs in the brain of a depressed individual. This arose as a result of the accidental discovery that drugs typically used to treat tuberculosis (TB) increased the levels of those monoamines in the brains of depressed patients and thereby elevated their mood. Indeed, this is the strategy behind most of the currently used antidepressant medications. By attempting to elevate the low levels of those monoamines it is hoped that it will readdress the balance of those mood-defining chemicals within the brain and thereby produce the action seen in non-depressed individuals.
Genetic & sociological theories of depression
Although the likelihood of an individual experiencing depression increases if a family member has been diagnosed with the condition, as yet no major gene has been implicated in the development of depression. There is a school of thought that the experiences that an individual has in their infancy may contribute toward the likelihood of experiencing clinical depression in later life. The forging of relationships between a child and their parent(s) is thought to be pivotal in the laying down of ideas about themselves, their parents, friends, family and the surrounding world. It is thought that if disruption occurs in the bonds formed in a young child’s life (e.g. parental divorce), then the attachment relationship between child and parent may become affected. This may manifest itself in later years by the individual experiencing feelings of guilt or low self-esteem and thereby increasing the likelihood of depressive illness.
Previously, individuals suffering from depression were treated with electroconvulsive therapy (ECT), long stays in hospital and/or prolonged sedation, which often made the problem worse. Stimulants such as amphetamines are no longer used as their side effects (anorexia, sleep disturbances, severe anxiety and psychotic episodes if taken over a prolonged time) have curtailed their use. Fortunately, the therapeutic options now available to depressed individuals are greater than those seen previously.
Current drugs used in the treatment of depression
The drugs presently used in the treatment of depressive illness vary in their chemical composition but they all work by increasing the brain concentration of important chemicals associated with mood and behaviour. They can be categorised as follows:
As there is little difference between these classes in terms of clinical effectiveness for the depressant profile for which they have been assigned, drug treatment should be initiated on a case-by-case basis tailored for each patient’s unique depressive profile.
Each of these classes of antidepressant will be considered in turn detailing their mode of action, their usefulness and side effects.
Tricyclic Antidepressants (TCAs) include the drugs amitriptyline, clomipramine (Anafranil®), dosulepin (Prothiaden®), lofepramine and trimipramine (Surmontil®). They are termed “tricyclic” on account of their basic chemical structure consisting of three adjacent rings. In the past, these compounds were the drugs of choice in treating clinical depression before being superceded by more selective medications. They act by hindering the removal and breakdown of important mood altering neurochemicals in the brain (dopamine and serotonin) and are most effective for moderate to severe depression associated with sleep disturbances, lethargy and loss of appetite. In practice, there is little difference between TCAs in terms of their clinical effectiveness in treating depression with the choice of drug determined by the most acceptable or advantageous side effect profile shown. For example, TCAs that have calming or sleep-inducing properties (e.g. Prothiaden ® or Surmontil®) may be more advantageous in depressed patients exhibiting agitation and/or individuals who find it difficult to sleep at night.
There is an approximate 2-4 week delay between the initiation of treatment with TCAs and evidence of clinical benefit. Patients need to be closely examined in the early stages of treatment to assess for compatibility and to monitor for any suicidal thoughts or self-harming tendencies.
Initiation of treatment
Unfortunately, between 10-20% of patients do not gain any clinical benefit from TCA treatment and therefore other treatment strategies need to be adopted. For initial dosing it is important to give a sufficient concentration of drug that will elicit a favourable clinical response without causing undesirable side effects. However, starting with low doses in the elderly is advisable due to the likelihood of this section of the population suffering from the type of side effects typically associated with TCAs (e.g. constipation and problems with vision – see below for a more comprehensive list).
The TCAs have a long lasting action in the body and therefore taking one dose of medication daily is typically sufficient. Indeed, taking the medicine at night takes advantage of the sedative properties of this class of antidepressant.
Contra-indications of TCA treatment
Not all patients are suitable candidates for TCA treatment. Treatment with this class of antidepressant drug is not recommended in patients recovering from a recent heart attack or who suffer from an irregular heart beat (arrhythmia). In addition, patients with severe liver disease or who suffer from bipolar illness (mania alternating with depression) are also unsuitable candidates for this line of therapy.
Cautions with TCA therapy
Certain patient populations can be treated with TCA medication when deemed necessary but must be closely monitored to prevent the occurrence of serious side effects or aggravating co-existing medical problems.
For example, these drugs can increase the chances of a patient suffering from an epileptic seizure either by lowering the conditions required for a seizure event to take place or by interacting with their anti-epileptic medication. Many TCAs cause drowsiness and therefore care must be exercised in individuals who drive or who operate heavy machinery. In addition, due to the risk of inducing irregular heartbeats, TCA therapy must be used with caution in patients with heart problems, diabetes or thyroid disorders. Furthermore, patients suffering from eye conditions, chronic constipation or problems urinating must be carefully assessed prior to the initiation of treatment. This is due to the ability of TCAs to relax the smooth muscle of the eye, gut and the bladder. Relaxation of the eye muscle inhibits drainage of liquid from the eye leading to increased pressure within the eyeball and may cause glaucoma. Relaxing the muscle of the gut used for transporting waste products from the diet towards defecation can lead to constipation and therefore may worsen the effects already seen in patients suffering with chronic constipation. Finally, relaxation of the bladder muscle will inhibit the ability to urinate leading to retention of the urine in the body. While this may be an advantage in patients who suffer from urinary incontinence, it can pose a serious problem in men who have blocked urinary flow due to an enlarged prostate gland.
Side effects of TCA therapy
Some of the side effects of this class of antidepressant have already been discussed. These and other side effects experienced by patients include:
Withdrawal of treatment
Where possible TCAs should be withdrawn slowly. As all antidepressants have the potential to cause unwanted effects upon withdrawal of the medication (especially if withdrawn suddenly) it is advised to gradually reduce the dose over a period of at least 4-6 weeks.
Monoamine Oxidase Inhibitors (MAOI’s) are much less frequently prescribed than they once were due to their potential to cause seriously high blood pressure in patients as a consequence of dietary and/or drug interactions with this class of antidepressant. Despite this they are still occasionally used, moclobemide (Manerix®) especially in patients in whom other antidepressant medication has failed to yield any clinical benefit. Drugs of this class appear to be beneficial in atypical depression, whereby a depressed patient experiences symptoms (e.g. weight gain, oversleeping) that are opposite to those usually seen with "typical" forms of the condition. They are also used in treating depression associated with certain phobias and social anxiety states.
They act by preventing the action of monoamine oxidase – an enzyme in the body that destroys the important neurochemicals responsible for mood elevation. It is thought that by inhibiting this enzyme’s action it allows these neurochemicals to act within the brain for longer and thus relieve the symptoms of depression.
Initiation of MAOI treatment
With older types of MAOIs, extensive patient counselling was required prior to the initiation of treatment. A full drug history and detailed analysis of typical dietary patterns were required in an attempt to prevent dangerously high blood pressure from the “cheese reaction”. This reaction occurs following dietary intake of foods such as cheese, fish and beans that are rich in the chemical tyramine. Under normal circumstances MAO destroys dietary tyramine in the gut wall. However, inhibitors of MAO prevent this from occurring, leading to rapidly raised levels of tyramine in the body that can ultimately culminate in life-threatening elevations of blood pressure. This dangerous reaction can also be seen following co-administration of MAOIs with other prescription drugs or over the counter medications that contain tyramine-like stimulants (e.g. nasal decongestants and certain cold remedies).
The only drug of this type that is still occasionally prescribed is moclobemide (Manerix®). Although it is reportedly less likely to induce the cheese reaction, it is still advisable for patients to avoid large amounts of tyramine-rich food and drinks and to avoid over the counter remedies that contain stimulants (eg pseudoephedrine (Sudafed®, Sinutab®, Lemsip Max Strength Sinus®, Nurofen Cold and Flu® to name but a few).’
For those patients in whom this treatment approach is deemed necessary, an initial dose of 150-300 mg is typically prescribed with the dosage increased according to clinical response.
Contra-indications associated with MAOIs
Treatment with MAOIs in depressed patients suffering from one or more of the following clinical conditions is not recommended:
In addition, MAOIs are not recommended in children or in debilitated patients.
Cautions with MAOI therapy
Initiation of MAOI treatment should not begin until at least 1-2 weeks after a tricyclic or related antidepressant has been stopped (five weeks in the case of the SSRI fluoxetine). This is needed to prevent the risk of “serotonin syndrome”, which is a life-threatening adverse reaction that can occur when two or more serotonin enhancing drugs interact to elevate serotonin levels to a toxic level. Symptoms of serotonin syndrome include excitability, nausea, convulsions, elevated body temperature, and a marked increase/decrease in blood pressure and coma, which may lead to death.
Conversely, other antidepressant medicines (including other MAOI’s) should not be started for at least two weeks after MAOI treatment has been stopped.
Moclobemide (Manerix®) is the most common MAOI inhibitor prescribed. Due to its short duration of action within the body no treatment free or “washout” period is required once treatment with this drug is stopped.
Side effects of MAOI medication
Adverse effects of MAOIs in addition to those experienced by either the cheese reaction or serotonin syndrome (see above) include:
Selective Serotonin Reuptake Inhibitors (SSRIs) are considered to be the first choice treatment option in the management of depressed patients (especially those in whom heart problems exist). This is partly because they have a greater safety profile than other antidepressants in terms of the dangers posed when taken in overdose and are generally better tolerated in affected individuals. Unlike other classes of antidepressant, the side effects typically seen with SSRI’s are largely limited to gastrointestinal (stomach) problems such as nausea, vomiting and constipation/diarrhoea.
Typical medicines of this class that are prescribed include:
It is thought that SSRIs elicit their antidepressant actions through the selective inhibition of serotonin reuptake and destruction in the brain. By inhibiting the removal of serotonin from its site of action, this important neurochemical can exert its mood altering properties for longer, thereby acting to relieve depressive symptoms. This class of antidepressant is particularly effective in the treatment of episodes of severe depression associated with sleep disturbances, lethargy and loss of appetite.
Initiation of Treatment
As with other classes of antidepressant there is an approximate 2-4 week delay between the initiation of treatment with SSRIs and evidence of clinical benefit. This delay in clinical response is thought to be due, at least in part, to an initial drug-induced inhibition of serotonin release in the brain that is then overcome following prolonged drug administration. Patients need to be closely monitored in the early stages of SSRI treatment to assess for drug compatibility and to monitor for any suicidal thoughts or self-harming tendencies. This is especially relevant in children and adolescent patients in whom the incidence of self-harming thoughts and actions is reportedly increased following treatment initiation with SSRIs. Initiation of SSRI treatment can be accompanied, in the first few days, by symptoms of nausea, agitation, anxiety and strange feelings of disassociation. Patients should be reassured that this is normal and will pass and is not a sign that their depression or anxiety is being made worse by their new medication.
Contra-indications of SSRI therapy
In an attempt to minimise the risk of developing serotonin syndrome it is advised that no patient should begin treatment with an SSRI while being treated with, (or within two weeks of stopping), a MAOI. However, certain MAOIs such as moclobemide (Manerix®) which exhibit a short duration of action within the body, allow for treatment with SSRIs to begin the day after MAOI therapy is terminated.
Cautions with SSRI therapy
SSRIs, like other classes of antidepressant, can lower the seizure threshold of epileptic patients thereby making an epileptic seizure more likely and easier to occur. Therefore, this class of antidepressant is to be used with caution in affected individuals – especially in those who have poor seizure control with their current anti-epileptic medication.
Despite SSRIs exerting less adverse effects on the cardiovasculature (heart and blood vessels), care must be exercised in patients who either have a specific disease of the heart or are more likely to experience heart problems as a consequence of a pre-existing medical complaint (e.g. diabetes, thyroid problems).
As the vast majority of the adverse effects associated with SSRIs are limited to the stomach and intestines, SSRIs should be used with caution in patients with a history of gastrointestinal problems or who are currently on medication that increases the likelihood of developing problems of the gut (especially bleeding).
Side effects of SSRI therapy
One of the main advantages of using SSRIs is that they have a lower incidence of the type of side effects seen with the older antidepressant drugs (i.e. less negative effects on the heart; lower incidences of dry mouth, urinary problems and sedation). However, SSRIs in addition to their dose-related side effects on the gastrointestinal system may give rise to the following symptoms:
Stopping SSRI therapy
When stopping SSRI medication a slow, gradual dose reduction tapered over a period of at least 4-6 weeks is recommended as abrupt withdrawal of drug may lead to flu-like withdrawal symptoms (e.g. sweating, palpitations, fatigue, headache, dizziness, and disturbance of the senses and/or vision). In practice this problem is seen with drugs with short durations of action in the body (e.g. paroxetine and sertraline) and less likely to be seen with longer acting SSRIs such as fluoxetine.
As their name suggests, Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) selectively inhibit both serotonin and noradrenaline reuptake and destruction from nerve terminals in the brain. Drugs of this class, while sharing much of the clinical profile seen with SSRIs, differ from that seen with TCAs and the MAOIs on account of their lack of action on other neurochemical systems susceptible to these “older” antidepressants. Consequently, they have a comparible toxicity profile to that seen with SSRIs and exhibit lower toxicity in comparison to TCAs and MAOIs.
They are used clinically in the treatment of major episodes of depression and in depressed individuals with accompanying anxiety disorders. Drugs of this class typically prescribed include:
It is thought that SNRIs elicit their antidepressant actions through the selective inhibition of serotonin and noradrenaline reuptake and destruction from nerve terminals in the brain. By inhibiting the removal of these mood-elevating chemicals from their site of action, these important neurochemicals can exert their antidepressant actions for longer. Moreover, by positively balancing the actions of these two neurochemicals it is thought that a better balance of mood enhancement occurs in the brains of depressed patients.
SSRIs vs. SNRIs
The SNRIs were introduced to the market more recently than the SSRIs and consequently there are relatively fewer of them. The initiation of SNRI treatment carries the same problems encountered with SSRIs (i.e. a delay between treatment initiation and the emergence of clinical benefits, a washout period between SNRI treatment and MAOIs and close monitoring of children/adolescents, along with the side effects mentioned above in the first few days of treatment). Furthermore, the side effects of SNRIs are reportedly similar to those experienced with SSRIs and include negative sexual side effects (delayed ejaculation, reduced libido (desire to engage in sexual activity) and difficulty in reaching an orgasm).
Contra-indications of SNRI therapy
As the pharmacological actions of SNRIs differ from that seen with SSRIs only in terms of their ability to elevate noradrenaline levels, most of the contraindications indicated for SSRIs are also applicable to SNRIs. As SNRIs cause an accompanying increase in noradrenaline in addition to serotonin, subtle criteria that define the contraindications between SNRIs and SSRIs are attributed to the effects of elevated noradrenaline levels in the brain. Consequently, patients with a history of high blood pressure and/or heart disease should have their blood pressure controlled prior to treatment with SNRIs and then closely monitored throughout their exposure to this class of antidepressant. In addition, SNRIs have also been associated with cases of severe liver disease and therefore should not be prescribed to patients with a history of chronic alcohol use or pre-existing liver problems.
Cautions with SNRI therapy
Treatment with SNRIs offers the same considerations as those experienced with SSRIs. In addition, patients with glaucoma must be closely monitored throughout their treatment with SNRIs.
Side effects of SNRI therapy
As the SNRIs and SSRIs both share the ability to elevate serotonin levels, they consequently exhibit similar side effects, albeit to varying degrees. The most common problems encountered include nausea, dry mouth, sexual dysfunction, headache, sleep disturbances, sweating, loss of appetite/weight and constipation. Accompanying side effects encountered include vomiting, dizziness and urinary retention.
Withdrawal of SNRI medication
As with SSRIs, stopping SNRI treatment abruptly usually leads to withdrawal symptoms which include heightened anxiety states and flu-like symptoms. Therefore, it is recommended that a slow tapering of the dose over a period of several weeks accompanied by close monitoring is performed. Withdrawal symptoms are typically seen in all of the SNRIs currently available on the market on account of their relative short duration of action and rapid clearance from the body following stopping of treatment.
Drugs of this class that are typically prescribed include:
With the exceptions of Reboxetine and Trazodone, atypical antidepressants elicit their antidepressant actions through a mechanism that does not appear to involve the inhibition of serotonin or noradrenaline reuptake and removal from nerve terminals in the brain. In general these drugs do not cause the same range of side effects seen with most other antidepressants and because they do not exert the same negative effects on the heart, they are considered safer when taken in excessive amounts (i.e overdosage).
Agomelatine is thought to exert its antidepressant actions through a mechanism that involves the increased release of dopamine and noradrenaline in a region of the brain that is heavily implicated in mood and emotional behaviour. It does not affect brain serotonin levels and is not thought to affect the reuptake and destruction of important mood-altering neurochemicals such as dopamine and noradrenaline.
Although more commonly used in the treatment of psychosis and schizophrenia, flupentixol has antidepressant actions when given orally in low doses and is thought to exercise this effect through a mechanism that involves the inhibition of dopamine and/or serotonin regulatory processes in the brain. It is thought that Flupentixol increases dopamine and/or serotonin levels by removing the “brake” that normally governs the release of these important chemicals from nerve endings in the brain, which culminates in an increase in their concentration at their site of action.
Mirtazapine’s antidepressant effects are thought to be executed via a mechanism that is similar to that seen with flupentixol, in that a control mechanism that has a negative influence on noradrenaline and serotonin release is inhibited, thereby allowing for the facilitated release of important mood altering neurochemicals within the brain. Mirtazepine is also used in lower doses in combination with other antidepressants (most commonly SSRIs) to augment or improve the efficacy of the other antidepressant.
Reboxetine is thought to exert its antidepressant actions via a highly potent and specific inhibition of noradrenaline reuptake from its site of action. This allows noradrenaline to exert its antidepressant effects for longer, thereby removing the brain from its depressed state.
Trazodone is structurally unrelated to any other class of antidepressant and yet manages to elicit an antidepressant action through the inhibition of serotonin reuptake from brain nerve terminals at sub-therapeutic doses. It is thought to be effective in depressive illness accompanied by aggressive behaviour and associated anxiety states.
Hypericum (St. John’s Wort) is widely used as a herbal antidepressant. How Hypericum works in the treatment of depression is unclear. Hypericum has been shown to have monoamine oxidase inhibiting activity; however, whether this is relevant in practice is currently unclear. Concern has been expressed about its unrestricted use via internet herbal shops, due to the number of interactions which are associated with it.
These include interactions with:
Care should be taken by patients intending to take Hypericum and a doctor and or pharmacist should be consulted before taking this medicine.
The decision to initiate antidepressant treatment must be taken after a full examination of the individual patient’s depressive illness.
Treatment strategies adopted must be tailored for a specific patient, taking into account other existing medical conditions, current medication(s) full patient history and an acknowledgement of the side-effects likely to be encountered during therapy.
Treatment initiation must be accompanied by close monitoring in an attempt to evaluate clinical effectiveness and to prevent self-harm by the patient.
Drug dosing should be carefully increased until a beneficial effect is seen. If no effect is evident after approximately four weeks of treatment, then either direct substitution with another drug of the same class or careful tapering with a new drug is required to prevent undesirable withdrawal symptoms.
Prof. Peter Weedle is a community pharmacist and adjunct Professor of Clinical Practice at the School of Pharmacy, University College Cork. Peter has a wide range of interests in the area of pharmacy but in particular, medicine use by the elderly, drug interactions, legal and ethical matters. He is co-author of two books: Pharmacy and Medicines Law in Ireland and Medicines: A guide for everybody. This series is based on Medicines: A guide for everybody which was originally published by Penguin, London. Peter can be contacted at: email@example.com
Dr. Mark Ledwidge is a pharmacist with a research and teaching interest in Cardiovascular Disease. In particular, his interests include medication adherence in chronic illness, telemedicine and cardiovascular therapeutics. He is Director of Heart Failure Research in St Vincent’s University Hospital and Adjunct Senior Lecturer in the School of Medicine in University College, Dublin.
Dr. Andrew Fisher is a community pharmacist in Cork City, with an extensive research background in neurological disorder and disease. His particular areas of interest include the pathophysiology and treatment of basal ganglia disorders and epilepsy. Andrew has a wide range of interests within the field of pharmacy including patient compliance, pharmacovigilance and therapeutic drug monitoring.
Mr. Nigel Moloney is a Superintendent Pharmacist in Cork city. Nigel comes from a UK Hospital Pharmacy background and his primary interests are in Acute Medicine, Psychiatry and Risk Management. Nigel has published articles in the scientific press on Risk Management Quantification and Communication between Primary and Secondary Care.
Dr. John McAninly is a community pharmacist in Mallow, Co. Cork who worked in hospital and community pharmacy in the UK, before moving to Ireland. As a former teacher he has a special interest in pharmacy education.
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