Pharmacological Management of Major Depression in Older Adults - Essay Example

? "Pharmacological Management of major Depression in older adults using Selective Serotonin-Reuptakes Inhibitors" Serotonin-specific re-uptake inhibitors (SSRI) belong to the category of antidepressant drugs that have revolutionized the treatment of depression and significantly minimized the range of adverse effects enforced by the use of the tricyclics or MAOIs. The efficiency of this group has reinforced the belief that serotonin level disorders are the predominant pathophysiological change precipitating the onset of affective disorders. These drugs increase extracellular serotonin levels by inhibiting serotonin reuptake into the presynaptic cells. They have minimal effect on noradrenalin and dopamine activity, compared to the tricyclics or MAOIs. Some of the drugs, like fluoxetine, have a mood elevating effect when used in healthy individuals. Fluoxetine drug has the longest half-life amongst all approved SSRIs with drug and side effects persisting up to six weeks after the termination of therapy. Introduction Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache. Serotonin is also one of the mediators of the signs and symptoms of carcinoid syndrome, an usual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. Patients with non-operable tumor, take serotonin antagonist for a useful treatment. The diagnosis of depression still rests primarily on the clinical interview. Major depressive disorder (MDD) is characterized by depressed mood most of the time for at least 2 weeks and/ or loss of interest or pleasure in most activities. Additionally, depression is associated with sleep, as well as diet disturbances and deficits in cognition and energy. Thoughts of guild, worthlessness and suicide are common. Coronary artery disease, diabetes and stroke appear to be more common in depressed patients and depression may considerably worsen the prognosis for patients with a variety of comorbid medical conditions (Katzang, 2009; Rang, 2009; Kaushik, 2011). Reports by Centers for Disease Control and Prevention highlight the fact that antidepressant drugs were the most commonly prescribed medications in the USA. It is observed that American physicians have been increasingly inclined to use antidepressants to treat a host of conditions that patients have been increasingly receptive to their use. Major depression is commonly associated with a variety of medical conditions from chronic pain to coronary artery disease, panic disorder, generalized anxiety disorder (GAD), post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) specifically in older individuals or other related old age diseases which enhances the burden of depressive thoughts and also affects the quality or life. All these reasons paved the way for growth in the use of antidepressants ( Katzang, 2009; Rang, 2009). Comparison of SSRIs with Tricyclic Antidepressants (TCAs) - The first line of antidepressant treatment suggested for elderly population involves SSRIs (Selective Serotonin Reuptake Inhibitors). There are weak facts for this suggestion as studies carried out highlight the comparative usefulness, protection, acceptability, as well as success of SSRIs and TCAs suggesting that there are a few optional returns of both these drugs over one another. Moreover, there is always a potential danger of falls which is prevalent in elderly patients, hyponatremia, loss of weight and sexual dysfunction, as well as drug-drug interactions. Therefore, SSRIs and TCAs must be prescribed by physicians for elderly patients considering frequency and severity of depression (Herrmann, 2000). Pathophysiology of Major Depression Observations reveal that there is a tremendous shift that has been witnessed for understanding the pathophysiology of major depression. Initially, the amount of monoamines was considered to be the central to the biology of depression. Evidence suggests that neurotrophic and endocrine factors play a major role. Depression is classified as- Primary depression - The condition is not secondary to a psychological or medical cause. Secondary depression - This may be consequent to some primary medical illness such as disorders of the thyroid, Cushing syndrome, diabetes, influenza, pneumonia, irritable bowel syndrome, degenerative arthritis, systemic lupus erythematosus (SLE), neurological condition such as Parkinson's or Alzheimer's disease and chronic obstructive airway. CNS depressants (barbiturates and benzodiazepines), narcotic analgesics, anticonvulsants, beta blockers (those with high lipid solubility and greater ability to reach the CSF), antihypertensives, calcium channel blockers (nifedipine), levonorgestrel preparations used for contraception as intrauterine implants (Kaushik, 2011). Unipolar depression - The patient experiences the symptoms of depression alone. Bipolar illness - The patient has had at least one episode of mood elation, referred to as a maniac episode, along with classical symptoms of depression. The condition also includes patients who experience only manic episodes. Bipolar disorders should be properly diagnosed because antidepressant drugs can worsen the condition and because lithium and anticonvulsants such as carbamazepine have proven efficacy in treating the disorder (Kaushik, 2011). Cyclothymia- this comprises frequent episodes of depression and hypomania, interspersed with relatively normal periods lasting mot more than two months. This is now regarded as a mood disorder rather than a personality disorder (Kaushik, 2011). Causes Major theories that explain the pathophysiological events in the genesis of depression will help us understand the drug therapies designed to treat the condition, and their advantages and limitations- Biogenic amine hypothesis - It is the most widely accepted hypothesis and provides an explanation for most of the features of depression. This hypothesis implicates the monoamines noradrenaline and serotonin in the causation of depression. Monoamine deficiency is a key phenomenon that leads to the pathogenesis of depression. This theory has been amply supported by the therapeutic effectiveness of drugs that increase the monoaminergic levels in alleviating the symptoms of depression (Rang, 2009). The selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) increase the synaptic concentrations of noradrenaline and serotonin; serotonin reuptake inhibitors prevent presynaptic uptake and deregulation of serotonin while monoamine oxidase inhibitors prevent termination of the action of both noradrenaline and serotonin and therefore increase their levels inside the synaptic clefts. Although this hypothesis explains the pathophysiological changes involved in the causation of depression, it fails to explain the delay in the development of therapeutic response following administration of MAOIs and SSRIs. This delay of at least 2-4 weeks happens despite the drugs raising monoamine levels within a few hours of administration (Katzang, 2009; Rang, 2009). Receptors supersensitivity hypothesis - This hypothesis explains why there is a delay in the onset of antidepressant effects following the use of MAOIs, tricyclic antidepressant and SSRIs. According to this theory, chronic deficiency of neurotransmitters leads to increased leads to increased number and sensitivity of postsynaptic receptors. The antidepressants restore the increased sensitivities of postsynaptic receptors and the time taken for these drugs to act is directly related to the time required by them to correct the receptors supersensitivies induced by deficiency of the biogenic amines (Katzang, 2009; Rang, 2009). Serotonin-only hypothesis - This hypothesis emphasizes the role of serotonin as the principal neurotransmitter in maintaining mood; therefore, serotonin deficiency is the main pathophysiological event that leads to the development of depressive disorders. This hypothesis has been largely supported by the therapeutic efficiency of the SSRIs in alleviating the symptoms of depression. This hypothesis has, its failure to explain the delay in onset of therapeutic effect following administration of SSRIs. Moreover, this hypothesis minimizes the role of noradrenaline in maintaining mood (which has been completely contradicted by results from experimental studies) (Kaushik, 2011). Permissive hypothesis- This hypothesis advocates interaction between serotonin and noradrenalin and states that the relative rather than the absolute levels of these neurotransmitters is the key factor in regulating mood and emotional behavior. This hypothesis is based on observations that suggest that serotonin modulates the CNS effects of other neurotransmitters, thereby keeping them in check. This hypothesis further postulates a reduced level of serotonin in mood disorders. This removes the modulatory effect of serotonin on other neurotransmitters and allows them to exert their full range of CNS effects. The hypothesis proposes abnormalities in noradrenalin levels in patients with mood disorders (Kaushik, 2011). Antidepressant Agents Monoamine Oxidase Inhibitors (MAOIs) MAOIs inhibit the breakdown of monoamine neurotransmitters and thus alleviate the symptoms of depression. They are the first agents used for depression, but now their use is declined because of its tendency to interact with a large number of drugs as well as with dietary constituents with potentially serious outcomes (Kaushik, 2011; Katzang, 2009; Rang, 2009). Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs refers to a class of antidepressant drugs. These drugs block serotonin reuptake, these drugs are believed to possess neuroprotective (may promote neurogenesis in animal studies and protect against neurotoxicity caused by MDMA and fenfluramine), immunomodulatory and anti-inflammatory properties, which may contribute to their efficiency in treating conditions other than depression. SSRIs are also effective against anxiety disorders, phobic neuroses, obsessive compulsive disorder, bulimia nervosa and chronic pain syndrome, and also for irritable bowl disease (Kaushik, 2011; Katzang, 2009; Rang, 2009). Mechanism of Action - Like other antidepressants the SSRIs are incapable of exerting their antidepressant effect immediately following administration. One mechanism proposed for this delay (of weeks) is that increased serotonin levels in the synapses secondary to their reuptake inhibition (caused by the use of these drugs) stimulates the presynaptic serotonin autoreceptors. This stimulation leads to a paradoxical decline in serotonin release and activity, an effect that is neutralized over time by a down-regulation of these pre-synaptic serotonin autoreceptors. Moreover, raised synaptic serotonin concentration may be associated with a down regulation of post-synaptic serotonin receptors. However, with the progression of treatment fewer number of postsynaptic serotonin receptors with increased serotonin concentration in synaptic cleft available to act on these receptors leads to increase in serotonin concentration acting on each individual receptors; this is an effect that may restore normal serotonin transmission, which is believed to be jeopardized in patients with depression (Kaushik, 2011; Katzang, 2009; Rang, 2009). Adverse Effects The main advantage of this group of antidepressant is lower profile of adverse effects as compared to tricyclic antidepressant. Selective serotonin reuptake inhibitors have a wider therapeutic index. Adverse effects are more common during the first few weeks of the therapy. They are mild and termination of therapy is not required. They are as follows- Nausea, dizziness, headache, anxiety, lethargy, fatigue, malaise, insomnia, vivid dreams, drowsiness, tremors, diarrhea, aggressive behavior, hypomania or mania, sexual dysfunction like decreased libido, erectile dysfunction, ejaculatory problems in men (Kaushik, 2011; Katzang, 2009; Rang, 2009). Increased libido and menstrual abnormalities in women, loss of appetite, weight loss, increased or decreased sweating, orthostatic hypotension more in older patients as compared to younger patients, akathisia, seizures (Kaushik, 2011; Katzang, 2009; Rang, 2009). Increased suicidal behavior in younger patients as compared to older individuals. These drugs can cause hepato and nephro toxicities which is more common in older individuals. Therefore complete checkup of liver function and kidney function tests are required. These drugs can even cause serotonin syndrome (Kaushik, 2011; Katzang, 2009; Rang, 2009). As depression and bone fragility (because of osteoporosis) are both common in elderly patients (over 60 years), SSRI are contraindicated in elderly patients. Many studies have shown presence of 5-HT receptors and 5-HT transporters in both osteoblasts and osteoclasts, so SSRIs may increase the incidence of fractures in elderly (Lerner, 2005). There is also an increased incidence of extrapyramidal syndrome in elderly. The probable reason may be because of inhibitory influence of serotonin on dopaminergic neurotransmission (Arya, 1994). Treatment Guidelines in Elderly Patients In mild depression psychotherapy should be considered and patient should be closely monitored for 2- 3 weeks. If condition does not improves or worsens then antidepressants like selective serotonin reuptake inhibitors should be the first line of drugs. As liver and kidney function deteriorate with advancing age, i.e. more than 65 years, doses of selective serotonin reuptake inhibitors should be titrated as per their liver and kidney function tests. Doses of Selective Serotonin Reuptake Inhibitors in Adults Drugs Usual Therapeutic dose (mg/ day) Citalopram 20-60 Escitalopram 10-30 Fluoxetine 20-60 Fluvoxamine 100- 300 Paroxetine 20- 60 Sertraline 50- 200 (Katzang, 2009). Elderly patients may also take medications for other associated diseases, therefore the selection of SSRIs should be based on minimal interaction with other drugs as SSRIs modulate many enzymes such as Cytochrome P450, which is responsible for metabolism of other drugs also (Kaushik, 2011; Katzang, 2009; Rang, 2009). Cases which do not respond to monotherapy with SSRIs, an addition of benzodiazepine can be considered for short period of 1- 4 weeks. Gradually benzodiazepine can be withdrawn. Therapy should not be stopped abruptly. References Arya DK (1994). Extrapyramidal symptoms with selective serotonin reuptake inhibitors. Br J Psychiatry. 165, 728-33. Herrmann, N. (2000). Use of SSRIs in the elderly: obvious benefits but unappreciated risks. Can J Clin Pharmacol. 7(2), 91-5. Katzang, B. G., Masters, S. B., Trevor, A. G. (2009). Basic & Clinical Pharmacology. 11th Ed. Tata McGraw- Hill Kaushik, M. (2011). Pharmcology Basic and Clinical Aspects. 1st Ed. Universities Press. Lerner, U. H. (2005). Serotonin reuptake inhibitors may increase the risk of osteoporosis. Lakartidningen. 102, 2746-9. (Article in Swedish). Rang, H. P., Dale, M. M. Ritter, J. M., Flower, R. J. (2009). Rang and Dale's Pharmacology. 6th Ed. Churchill Livingstone. Read More