Antidepressants mania

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

Patients with bipolar disorder have a high risk of suicide. Factors that increase that risk are early age at disease onset, high number of depressive episodes, comorbid alcohol abuse, personal history of antidepressant-induced mania, and family history of suicidal behavior.15 In those with bipolar disorder, 1 of 5 suicide attempts are lethal, in contrast to 1 of 10 to 1 of 20 in the general population. 

Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a pharmacologic mood switch to mania, although there is not complete agreement about such risk. Treatment guidelines suggest lithium or lamotrigine as first-line therapy.17,41 Olanzapine has also demonstrated efficacy in treatment of bipolar depression, and quetiapine is under review for approval of treatment of bipolar depression.42 When these fail, efficacy data support use of antidepressants. 

Guidelines agree that when antidepressants must be used, they should be combined with a mood-stabilizing drug to reduce the risk of mood switch to hypomania or mania.17,41 The question of which antidepressant drugs are less likely to cause a mood switch is not resolved. Anecdotal reports suggested bupropion may be less likely to cause this effect, but systematic reviews have not supported this conclusion. Prevailing evidence recommends that tricyclic antidepressants be avoided.41,43... 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

Mood stabilisers are used to regulate the cyclical change in mood characteristic of bipolar disorder, since they can attenuate both manic and depressive phases. Their main use is as a prophylactic for manic depression and unipolar mania. However, they can also be administered concomitantly with antidepressants for refractory (non-responsive) unipolar depression. 

Mundo E, Walker M, Cate T, Macciar-di F, Kennedy JL. The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder preliminary findings. Arch Gen Psychiatry 2001 58 539-544. 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

Lithium is effective for acute mania, but it may require 6 to 8 weeks to show antidepressant efficacy. It may be more effective for elated mania and less effective for mania with psychotic features, mixed episodes, rapid cycling, and when alcohol and drug abuse is present. Maintenance therapy is more effective in patients with fewer episodes, good functioning between episodes, and when there is a family history of good response to lithium. It produces a prophylactic response in up to two-thirds of patients and reduces suicide risk by eight- to 10-fold. 

Bipoiar Disorders. You must also distinguish the bipolar disorders from MDD. The distinction is particularly important in young adult patients given that nearly 10% of patients with an initial episode of major depression will go on to develop a bipolar illness. The devastating consequences of untreated mania coupled with the possibility that antidepressants may trigger manic episodes in susceptible individu-... 

More controversial is the occurrence of antidepressant-induced mania or hypo-mania. DSM-IV specifically states that manic or hypomanic episodes triggered by antidepressant treatment should not count toward the diagnosis of BPAD. However, clinicians have traditionally viewed antidepressant-induced switching from depression into mania as an unmasking of a preexisting BPAD that had previously been unrecognized and undiagnosed. 

In contrast to MDD, the bipolar disorders consist of episodes of depression and episodes of hypomania or mania. This poses a problem for treating the depressed phase of this illness, becanse, as noted earlier, antidepressants can trigger hypomania, mania, or mixed dysphoric mania and can increase the freqnency of manic episodes. Therefore, the hallmark of treating BPAD is the nse of mood stabilizers, with and withont snpplemental antidepressant therapy. Please refer to Table 3.16 for a comparison of the traditional mood stabilizers. 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

It appears that SSRls and bnpropion are less likely than TCAs to indnce mania. Venlafaxine, perhaps becanse of its dnal effects on serotonin and norepinephrine like the TCAs, also appears to increase the likelihood of switching into mania. Rarely, if ever, shonld an antidepressant be nsed in bipolar patients withont concomitant treatment with a mood stabilizer. 

If the depressive symptoms do not resolve when treatment with one of the aforementioned mood stabilizers has been maximized, adjunctive therapy with an antidepressant or second mood stabilizer should be considered. SSRIs and bupropion are well tolerated by bipolar patients and appear to hold less potential to induce mania than TCAs. Nevertheless, treatment with any antidepressant should not be started until it has been confirmed that the patient s mood stabilizer is at a therapeutic level. If treatment with two or more of these first-line antidepressants is unsuccessful, a MAOI should be considered. 

In reality, risperidone acts as an atypical antipsychotic at doses up to 4-6mg/day. At higher doses, risperidone begins to act more like a typical antipsychotic, and EPS can become a problem. The dose at which this occurs for individual patients is quite variable. In elderly patients, even low doses can cause EPS. Whether this risk for EPS translates into a risk for TD after long-term use remains unknown. There is now considerable evidence that risperidone is also effective in treating mania and in augmenting antidepressants in particularly low doses. 

For example, stimnlants can cause irritability. However, irritability can also resnlt from depression. So it is always important to rule out comorbid depression in the patient with ADHD before discontinuing the stimulant medication. If the irritability does resnlt from depression, then the obvious solution is to add an antidepressant to the stimnlant. Conversely, irritability can also be a symptom of emerging hypomania or mania. 

Numerous open studies, and seven controlled studies, have shown that valproate is effective in the treatment of acute mania. It has also been claimed to have an antidepressant action. Recent studies have shown that valproate is effective in the long-term treatment of bipolar disorder. 

Activation of psychosis or mania Antidepressants can precipitate manic episodes in bipolar manic depressive patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. 

AppetiteAA/eight changes Anorexia was reported for venlafaxine-treated patients. A dose-dependent weight loss often was noted in patients treated for several weeks. Manla/Hypomania During clinical trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. As with all antidepressants, use venlafaxine cautiously in patients with a history of mania. 

Mania/Hypomania As with all antidepressants, use nefazodone cautiously in patients with a history of mania. 

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