Applied Biological Principles in Mental Health: Depression - Case Study Example

Applied Biological Principles in Mental Health: Depression Introduction In this context, the patient is a 33 year old lady, mother of three Stephanie Bewley who has a history of unipolar depression and currently, she is in a state of total despair and has suicidal ideation. Her only noted form of family support is that of her mother. Recurrent episodes of major depression, also known as unipolar depression is a common and serious illness. When depression is combined with manic episodes, it is known as bipolar disorder. There are also other forms of depression such as dysthymic disorder where patients have chronic, mild depression most of the time with no discrete episodes and cyclothymic disorder where there are alternating periods of hypomania and periods with mild to moderate depressive symptoms. Major depressive disorder or unipolar depression accounts for approximately 4.4% of the total overall global disease burden and in the US, the prevalence of unipolar depression is from 5.4% to 8.9% and 1.7% to 3.7% for bipolar disorder (World Health Organization, 2002; Narrow et al, 2002; Kessler et al, 1994). Structure and function of the brain involved in depression In regards to the areas of the brain involved, Mayberg (2001) has found in his work that the dorsal neocortical structures of people with depression are hypometabolic whereas the ventral limbic structures are hypermetabolic. This has been proven by experimentally inducing sadness in normal subjects and the changes are immediately reversed when the sadness stimuli is removed. In depressed patients, it has been shown that this abnormality is persistent. Frontostriatal pathways in the brain also mediate positive affect-guided anticipation and abnormalities within this area might result in the inability to anticipate incentives, thus predisposing one to depression. When a reward is presented in the form of a stimuli, the left medial orbitofrontal cortex is activated. Additionally, the anterior cingulated gyrus has connections to brain structures which are impaired in people with depression (Bush et al, 2000). The perigenual cingulated which normally assesses the conflicts between current and normal brain function as well as information processing which leads to motivational consequences and also the dorsal cingulated which monitors the competing responses and modulates attention is also impaired in people with depression (Bush et al, 2000). Dysfunction within the frontostriatal area also predispose people to developing depression later on in life as executive dysfunction which is a clinical expression of frontostriatal abnormality is common in people who develop depression in late adulthood (Lockwood et al, 2002). Kumar et al (2004) have found in their research that molecular changes at the macro level within the genu and splenium of the corpus callosum, the caudate nucleus and the putamen can lead to depression. Furthermore, reduction in glia of the anterior cingulated and abnormalities within the neurons of the dorsolateral cortex have been found in patients with depression (Ongur, 1998). Abnormalities of the brain also affect the presentation, the course of depression as well as the response of depression towards medication. For example, the frontostriatal dysfunction mentioned earlier increase psychomotor retardation and results in a greater expression of apathy within patients with depression (Alexopoulos, 2002). Executive dysfunction also results in a slower and poorer response to antidepressants (Simpson, 1998). Hypometabolism of the anterior cingulated was found in patients who responded poorly to the treatment of major depression and they were more likely to even resist maximal doses of antidepressants (Mayberg, 2001). The amygdala which is involved in mediating emotions in response to aversive stimuli as well as signaling to areas of the brain which are responsible for coping behavior and autonomic functions of the body has also found to play a role in depressive patients (LeDoux, 1993). This was shown in studies which found a correlation between the degeneration of the amygdala with time as well as damage to this structure via a stroke which led to depression. During periods of chronic medical illnesses, the activity within the amygdala increases secondary to increased levels of cortisol which then leads to bouts of depression. Another structure within the brain which is involved in depression is the hippocampus. Sheline (2003) has found that the volume of this structure is reduced in the first episode of major depression. This acute reduction is prolonged in patients with long term or lifetime depression and the decline in hippocampal volume has been well documented in patients who had suffered from a first episode of major depression and unresponsive to antidepressants (MacQueen, 2003). Pathophysiological process of depression These gross anatomical changes which can lead to depression cannot function on its own as various studies have also found a strong link between depression and the neurotransmitters and chemicals which govern normal brain function. In this context, the discussion would be between depression and norepinephrine as well as serotonin. It is important to note that current knowledge regarding norepinephrine is that the decreases or elevations in norepinephrine do not alter moods in everyone. However, the link has been found because the norepinephrine pathway which originate in the brain stem primarily at the locus coeruleus and project to other parts of the brain including the limbic system play an important role in regulating emotions. According to Guyton and Hall (1993), in a person without depression, monoamines, like all neurotransmitters travel from the presynaptic cell across the synaptic cleft and attach itself to the postsynaptic cell. This would lead to changes within the cell which either inhibit or stimulate the firing of the postsynaptic cell. The effect of the neurotransmitter depends on the strength as well as the concentration of its receptors on the postsynaptic cells. Monoamine oxidase within the cells can also affect the synaptic neurotransmitter levels by degrading monoamines which then reduce the amount of these molecules available for release. Research has shown that low levels of synaptic norepinephrine which is represented by low levels of its metabolites in the urine or cerebrospinal fluid are often found in patients with depression (Klimek et al, 1997). These low levels are also found in postmortem studies where there are low densities of norepinephrine receptors in suicide victims. There is also a mismatch between the number of post and presynaptic receptors as when transmitter molecules become scarce in the synapses, postsynaptic receptors would increase in number to pick up any available signal but it is ineffective. Additionally, a new study has found that drugs which are able to selectively block the reuptake of norepinephrine can improve depression in many people (Delgado and Moreno, 2000). The second link is between serotonin and depression. It has been found that defects within serotonin-linked pathways within the brain would adversely affect norepinephrine signaling. Serotonin-producing neurons project from the raphe nuclei in the brain stem to the neurons in various parts of the brain including that of which that control and secrete the release of norepinephrine. Thus, when there are low levels of serotonin, this may affect the functioning of other neurons as serotonin-producing cells extend into many areas of the brain thought to be involved in emotions as noted above such as the amygdala and hypothalamus. A current finding has found the link between low synaptic serotonin levels and depression in which the cerebrospinal fluid in patients with depression, especially those with suicidal intent contain a lower than normal level of a serotonin metabolite (which represents a lower level in the brain) (Owens and Nemeroff, 1994). The levels of a surface molecule unique to serotonin releasing cells are also lower in depressed patients. The link between serotonin and depression can be further strengthened by the effectiveness of drugs which block presynaptic reuptake of serotonin. For example, tricyclic antidepressants have been found to decrease serotonin reuptake and also causes a consequential rise in serotonin levels in the synapses. Newer drugs such as the selective serotonin reuptake inhibitors (SSRIs) also support this hypothesis regarding the link between serotonin and depression as these drugs do not affect other neurotransmitters (Worthington, 2005). Studies have also found the link between depression and the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is involved in managing the body’s response to stress and when faced with one, the hypothalamus increases the production of corticotropin releasing factor (CRF) which then induces the pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH would then direct the adrenal to release cortisol and this prepares the body to face a fight-or-flight situation. However, if the HPA axis is stimulated and activated for long periods, it may actually cause depression. Early studies have shown that depressed patients not on any medication have much higher than normal levels of cortisol in their blood, urine as well as cerebrospinal fluid (Ehlert et al, 2001). With the development of better imaging techniques, studies have also shown that depressed patients have HPA axis hyperactivity. The magnification of CRF levels in cerebrospinal fluid in depressed patients has also been demonstrated. With treatment including drugs as well as electroconvulsive therapy, the levels of these hormones decrease. In postmortem studies, it has been found that there is an exaggeration in the number of CRF producing neurons as well as the expression of the CRF gene which directly results in an elevated CRF production. Studies involving animals which were given CRF to the brain have also noted signs and symptoms of depression including insomnia, decreased appetite, anxiety and decreased in libido (Bale and Vale, 2004). Clinical relevance of the theories in practice With the information, these pathophysiological processes as well as abnormalities of the brain anatomy involved in depression can be applied in clinical practice to manage depression. In this context, we would be able to know if a patient would be predisposed to depression based on family history and knowledge can also be obtained on how to overcome resistant forms of depression. About 50% of moderate to severe forms of depression can be improved with antidepressant treatment and the choice of the antidepressants would be defined by their classes of action. For example, some antidepressants work by amplifying the effect of serotonin or norepinephrine signaling by inhibiting the reuptake process at the synapses whereas drugs such as SSRIs and SNRIs inhibit the reuptake of serotonin and norepinephrine. MAOIs inhibit monoamine degradation via monoamine oxidase A or B. Pharmacology of drug groups One of the antidepressants used would be the monoamine oxidase inhibitors (MAOI) and the tricyclic antidepressants (TCA). The mechanism of action of an MAOI is to increase the level of available monoamine transmitters such as dopamine, norepinephrine as well as 5-hydroxytryptamine (5-HT) by blocking their metabolism. Classical forms of MAOIs such as phenelzine, tranylcypromine and isocarboxacid are irreversible and non-selective compared to newer ones which can be selective as well as reversible (Sambunaris et al, 1997). TCAs are one of the widest and most effective forms of antidepressants used globally. Basically, TCAs are combination of drugs which include drugs which inhibit serotonin and norepinephrine reuptake, activate the anticholinergic-antimuscarinic pathway, antagonize alpha-1 adrenergic activity as well as stimulate antihistamine activity. TCAs can also inhibit sodium channels if given in doses higher than that of the recommended dosage which can lead to seizures and arrhythmias. In depression, it is the serotonin and norepinephrine reuptake inhibition which is therapeutic. The selectivity and strength of inhibition of the 5-HT compared to norepinephrine transporters differ from the various types of TCAs. Side effects of TCAs can be explained by the mechanism of action for example antihistamine side effects (sedation), antiadrenergic effects (hypotension, tachycardia, arrhythmias) and antimuscarinic effects (dry mouth, constipation) (Stahl, 1998). The second group of drugs used to counter depression would be the selective serotonin reuptake inhibitors (SSRIs). As the name implies, SSRIs selectively inhibit the transport of serotonin which then causes the increase in serotonin available at the dendritic area. With long term usage of SSRIs, there is a sustained increase in the levels of serotonin which would then lead to the desensitization of the somatodendritic serotonin 1A autoreceptors. When this desensitization occurs, the neuronal impulse flow would no longer be inhibited by serotonion and in turn, neuronal impulse flow is regenerated which directly causes the release of serotonin from the axonal terminals (Blier et al, 1987). This mechanism allows SSRI to counter depression but at the same time, it also can cause tolerance to the side effects of SSRIs. In clinical usage, SSRIs are used to offer patients with depression a strong but delayed disinhibition of 5-HT transmission. Additionally, SSRIs also work on the midbrain raphe to the prefrontal cortex to cause antidepressant effects. Some of the side effects of SSRIs include sexual dysfunction as well as gastrointestinal disturbances (Foote and Morrison, 1987). The 5-HT receptors involved in the serotonergic pathways are involved in mediating these side effects, for example in regards to the development of sexual dysfunction, there is a link between serotonin and dopamine with serotonin inhibiting the sexual functioning whereas dopamine enhances sexual functioning. Thus, SSRIs which disinhibit the serotonergic pathway that innervate the dopamine systems cause sexual dysfunction (Balon, 1997). SSRIs also cause akathisia due to the stimulation of the 5-HT receptors in the serotonin pathway that projects to the basal ganglia. Serotonin inhibits the release of dopamine from the area of the brain and thus, by increasing serotonin, this produces a dopamine deficient state which leads to akathisia. SSRIs may also induce insomnia due to the stimulation of the 5-HT pathway found in the brain stem’s sleep centers. In regards to the gastrointestinal side effects, the stimulation of the brain stem’s vomiting center as well as the pathway to the hypothalamus and the gastrointestinal tract has been hypothesized to cause these problems (Costall et al, 1990). There are newer forms of antidepressants in the market such as serotonin/norepinephrine/dopamine reuptake inhibitors (SNRI/NDRI). For example, venlafazine is dose dependent and at low doses, it functions as an SSRI and at medium to high doses, there is also a norepinephrine effect whereas at very high doses, there is a dopamine effect (Bolden-Watson and Richelson, 1993). The side effects of the SNRIs and NDRIs are similar to that of the SSRIs. Another group of drugs would be the serotonin antagonist and reuptake inhibitors (SARIs). Drugs in this class include nefazodone and trazodone. The difference between SSRIs and SARIs would be that the 5-HT receptors are blocked by SARIs whereas it is stimulated by the SSRIs. Thus, the SARIs do not cause some of the side effects of SSRIs such as akathisia and insomnia (Stahl, 1998). Bupropion is an NDRI and this drug does not involve the serotonin pathway as it acts selectively on dopamine and norepinephrine. The clinical action of bupropion is that is boosts both dopamine and norepinephrine but at the same time, there are side effects of psychosis and seizures in high doses (Davidson and Conner, 1998). Bupropion is also used in the treatment of smoking cessation as well as attention deficit hyperactivity disorder (ADHD) (Casat et al, 1989; Goldstein, 1998). Mirtazapine is a norepinephrine and serotonin antagonists (NASAs). Thus, its mechanism of action involves the norepinephrine and serotonin pathways and are also selectively directed away from the 5-HT receptors. Similar to nefazodone, mirtazapine does not cause the side effects of SSRIs but can cause sedation and weight gain (Stahl, 1997). According to DeBattista and Schatzberd (2000), reboxetine is a norepinephrine specific reuptake inhibitor (NRI). It has a high affinity to the norepinephrine transport system and little affinity for other neurotransmitters such as serotonin and dopamine. Studies have shown that when norepinephrine reuptake reduces symptoms of depression, regulation of norepinephrine would be the factor which actually improves a patient’s interest, concentration and feelings of hopelessness. Thus, reboxetine is useful for patients with symptoms of depression as well as anxiety. The side effects of reboxetine include dry mouth and constipation but is relatively well tolerated in many patients. Tianeptine is a serotonin reuptake enhancer. Basically, it increases the uptake of serotonin in the presynaptic area and does not have any of the side effects of the 5-HT system. Tianeptine can be grouped within the mid-level antidepressants and has no anticholinergic side effects but rare side effects such as dry mouth and gastrointestinal disturbances have been reported (Loo and Deniker, 1988). In addition to the usage of antidepressants, there should also be adjunctive medications which can help to augment the effect of antidepressants as well as target other components of the patient’s symptoms including delusions because depressed patients who present with delusions may acutely go into a manic state. One of the adjunctive medications which can be used would be lithium. Lithium is basically a mood stabilizer and it prevents the recurrence of depression as well as mania. Bauer and Dopfmer (1999) have found that the condition of half the patients who do not have an adequate response to a single type of antidepressant improve when lithium is added to the treatment regime. Additionally, lamotrigine which is an anticonvulsant and works by reducing the glutamatergic activity has been used effectively in major depression (Barbosa et al, 2003). Additionally, both typical and atypical antipsychotics can also be added to the antidepressant treatment regime. Typical antipsychotic agents such as chlorpromazine block the dopamine D2 receptors whereas atypical antipsychotic agents such as clozapine act as –HT antagonists. Antipsychotic drugs are combined with antidepressants to treat depression with psychotic features whereas atypical antipsychotic drugs are used to in treatment-resistant depression (Rothschild et al, 2004; Kennedy and Lam, 2003). Drug treatment and pharmacology Utilizing the knowledge above, Stephanie Bewley is in need of a therapeutic strategy which requires a multimodal approach including pharmacotherapy, psychotherapy as well as education. There are three phases of treatment which are the acute, continuation and maintenance phase. During the acute phase of treatment, the goal is for remission and this is one of the characteristics which we have to look for in order to note that the patient has improved. This can be gauged from the patient herself as well as her family members. Hospitalization is needed if there is severe signs and symptoms of delusions as well as a high risk of suicide. SSRIs and other newer antidepressants with a greater safety margin are first line drugs for the treatment of depression rather than TCAs because of the lower risk of anticholinergic and cardiovascular side effects (Peretti et al, 2000). This phase usually lasts 6-10 weeks and the patient should be evaluated weekly until there is significant improvement. In Stephanie, there is suicide ideation and thus, these may take longer to improve compared to symptoms of sleep and appetite (Greco et al, 2004). If treatment response to SSRIs is unsatisfactory (less than 50% improvement), then, a change in the type of medication is needed. Rush and Kupfer (2001) have noted that if there is no improvement after four weeks of treatment with a particular type of medication, the end response is going to be inadequate and thus, augmentation has to be done as soon as possible. If Stephanie is unresponsive to the SSRIs, then, switching to another antidepressant from a different class would lessen chances of the risk of adverse drug reactions which are usually seen in polypharmacy. Additionally, the switch to a new antidepressant from the same class may also be used because it has been shown that patients who do not have a response to one SSRI have a 40-70% change of improvement of response with a second SSRI (Thase and Rush, 1997). As noted earlier, augmentation with other agents may enhance the efficacy of antidepressants. Two to four weeks of treatment with lithium during the acute phase may show a response and lamotrigine may be added if she does not respond to fluoxetine (Barbosa et al, 2003; Bauer et al, 2003). Additionally, if Stephanie is suffering from insomnia, there is also a role for benzodiazepines which has been shown to improve this symptom in up to 60% of patients (Furukawa et al, 2001). The second phase would be the continuation phase. This lasts between six to nine months after the induction of remission and the aim is to restore prior normal functioning and to prevent relapse. Similar medications and doses are used within the acute phase is used during the continuation phase (Rush and Kupfer, 2001). If there are no relapses or recurrences during the continuation phase, the drug regime can be discontinued for most patients but we should be aware that early discontinuation is associated with a 77% higher risk as continued to continuation of treatment (Melfi et al, 1998). Thus, it would be safer to taper the medication over a few weeks and to continuously monitor the patient for symptoms of relapse. The caretaker as well as health personnel should also be aware of the discontinuation syndrome which is represented by gastrointestinal symptoms, anxiety as well as irritability (Schatzberg et al, 1997). The third phase would be the maintenance phase which includes treatment for 12-36 months and this regime would reduce recurrence by two thirds. The duration of maintenance would be dictated by the history of depression and may be increased if it is more severe or has recurred (Geddes et al, 2003). The choice of medication would be the first drug which brought about remission and is well tolerated by the patient. In this context, all antidepressants including TCAs, SSRIs and MAOIs help to reduce recurrence (Thies-Flechtner et al, 1996). Conclusion Depression is a disorder which can be treated but at the same time, monitoring is important. A multimodal approach would be best in this patient to achieve remission and to prevent future episodes. Thus, it is important for the caregiver as well as healthcare personnel to provide what is best suited for the patient and hopefully, she would be able to live a normal life. 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Geneva Worthington JJ, Kinrys G, Wygant LE, Pollacka MH. 2005. Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol; 20: 9-11 Read More