Treatment of depressive episodes

The drug therapy of depression differs in a number of critical points from that given to schizophrenics. Depressions are phasically occurring deviations from the norm that, in the majority of cases, show spontaneous remission, although this often may be only after a period of some months. The majority of depressives can be treated as outpatients a fact that explains why the illness generally does not make as severe an encroachment into the family and social surroundings of the patient as does schizophrenia. Outsiders are able to imagine what a depression must be like, or at least believe that they can everyone is occasionally sad. disappointed or devoid of hope. In the eyes of his fellow men and women a depressive consequently tends to be a person to be pitied but not one who is necessarily mad. 

None of today s antidepressants are devoid of side effects, which, for their own part, can intensify the feeling of illness and concern felt by the patient. Doctors consequently will not prescribe antidepressants unnecessarily, especially in older patients who react particularly sensitively to the mitral and peripheral effects of these substances. Many doctors even seem to tend to insufficient prescriptions according to a survey reported by Keller et al. (1982), 

Treatment of Depression with Newer Generation Antidepressants 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001), 

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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. 

Bipolar disorder For the treatment of depressive episodes associated with bipolar disorder. 

Some clinicians will add a variety of antidepressants, including SSRIs like Prozac, to the treatment of patients with bipolar disorder. Nearly all antidepressants can cause or worsen mania (chapter 7). Nonetheless, Eli Lilly managed to obtain FDA approval for Symbyax, a combination of Zyprexa and Prozac, for the treatment of depressive episodes associated with bipolar disorder. In reality, Prozac should not be prescribed to patients with bipolar disorder, given the frequency with which SSRIs cause and exacerbate manic reactions. 

It is indicated in the treatment of depressive episodes associated with bipolar disorder. A combination of an antipsychotic drug and an antidepressant may be useful in some cases, especially in depressed psychotic patients, or in cases of agitated major depression with psychotic features. The first combination antipsychotic/antidepressant (olanza-pine/fluoxetine Symbyax) was recently FDA approved in the United States for treatment of depressive episodes associated with bipolar disorder. However, antidepressants and stimulants are unlikely to reduce apathy and withdrawal in schizophrenia, and they may induce clinical worsening in some cases. Adjunctive addition of lithium or an antimanic anticonvulsant, such as carbamazepine, may add benefit in some psychotic patients with prominent affective, aggressive, or resistant symptoms. 

Optimize the dose of mood stabilizing medication(s) before adding on lithium, lamotrigine, or antidepressant (e.g., bupropion or an SSRI) if psychotic features are present, add on an antipsychotic ECT used for severe or treatment-resistant depressive episodes or for psychosis or catatonia... 

Plants affecting the serotoninergic neurotransmission are therefore interesting because of their potentials for the treatment of depression, which is the eighth leading cause of death in the United States. It is generally agreed that there is a correlation between diminished serotonin neurotransmission and episodes of major depression, and a number or inhibitors of serotonin-uptake inhibitors are available on the market, such as sertraline (Zoloft ). 

Non-motor signs of the disorder are also treatable with symptomatic medications. The frequent mood disorder can be treated with standard antidepressants, including tricyclics (such as amitryptiline) or serotonin reuptake inhibitors (SSRIs, such as fluoxetine or sertraline). This treatment is not without risks in these patients, as it may trigger manic episodes or may even precipitate suicide. Anxiety responds to benzodiazepines, as well as to effective treatment of depression. Long-acting benzodiazepines are favored over short-acting ones because of the lesser abuse potential. Some of the behavioral abnormalities may respond to treatment with the neuroleptics as well. The use of atypical neuroleptics, such as clozapine is preferred over the typical neuroleptics as they may help to control dyskinesias with relatively few extrapyramidal side-effects (Ch. 54). 

Lithium is the simplest therapeutic agent for the treatment of depression and has been used for over 100 years—lithium carbonate and citrate were described in the British Pharmacopoeia of 1885. Lithium therapy went through periods when it was in common use, and periods when it was discouraged. Finally, in 1949, J.J.F. Cade reported that lithium carbonate could reverse the symptoms of patients with bipolar disorder (manic-depression), a chronic disorder that affects between 1% and 2% of the population. The disease is characterized by episodic periods of elevated or depressed mood, severely reduces the patients quality of life and dramatically increases their likelihood of committing suicide. Today, it is the standard treatment, often combined with other drugs, for bipolar disorder and is prescribed in over 50% of bipolar disorder patients. It has clearly been shown to reduce the risk of suicide in mood disorder patients, and its socioeconomic impact is considerable—it is estimated to have saved around 9 billion in the USA alone in 1881. 

It is common for both the depressive and manic phases to occur simultaneously in what is termed a mixed state or dysphoric mania. During these mixed episodes, the patient s mood is characterized by symptoms of both a depression and mania. Mixed episodes often have a poorer outcome than classic euphoric mania and, as a rule, respond better to certain anticonvulsants and atypical antipsychotic drugs than to lithium. As many as 50% of admissions to inpatient psychiatric facilities for the treatment of manic episodes appear to be for mixed manic states. The recognition... 

Mania For the treatment of manic episodes of manic-depressive illness. Maintenance therapy prevents or diminishes the frequency and intensity of subsequent manic episodes in those manic-depressive patients with a history of mania. 

Treatment of individual episodes is described above. The treatment or monitoring of individual episodes of mania or depression should also take into account the risk of a swing to the opposite polarity induced by the treatment of the current episode (i.e., depression triggered by neuroleptic treatment of manic episode, or mania following antidepressant treatment). The speed of such a swing may take unwary physicians by surprise. 

Many of the children and adolescents seen for treatment of depression are experiencing their first depressive episode. Because the symptoms of unipolar and bipolar depression are similar, it is difficult to decide whether a patient needs only an antidepressant or concomitant use of mood stabilizers. As noted above, symptoms and signs such as psychosis, psychomotor retardation, or family history of bipolar disorder may warn the clinician about the risk of the child developing a manic episode. 

Shortly after iproniazid was shown to have antidepressant properties, imipramine was introduced as the first tricyclic antidepressant. These drugs received the name tricyclic because their structure contains three molecular rings. At first, imipramine was investigated as a possible treatment for the psychotic episodes associated with schizophrenia, a severe mental disorder that causes hallucinations and delusions, because it was chemically similar to another effective anti-schizophrenia drug. Imipramine did not reduce the severity of psychotic episodes, but it did elevate the mood of the patients who took it. In the late 1950s, it was released in the United States under the name Tofranil for the treatment of depression. 

Valproic add (Depakote 6 ) is an anticonvulsant with good antimanic action that is especially suited for patients with rapid cycling and mixed episodes (Bowden et id., 1994). However, it is a poor antidepressant, necessitating the use of a low-dose SSRI in the treatment of depression that may occur in the course of bipolar disease. 

One British study found amphetamine to be no different than placebo in the treatment of depressed outpatients (188) a second study found amphetamine less effective than phenelzine and no better than placebo (189) and a Veteran s Administration (VA) study found dextroamphetamine no more effective than placebo in hospitalized depressed patients (1,90). Uncontrolled clinical evidence indicates that amphetamine may occasionally be of value, but, except for a mild, early, transient benefit, there is no evidence that amphetamine can ameliorate moderate-to-severe depressive episodes. 

The study by Elkin et al. (391) from the National Institute of Mental Health Treatment of Depression Collaborative Research Program suggested that antidepressants had superior efficacy in the treatment of moderate to more severe episodes of major depression (i.e., 17-item HDRS score of 20 or more). In response to that claim, DeRubeis et al. (396) performed a metaanalysis of four studies and found that CBT was as effective as several different antidepressants in such cases. More recently, Keller et al. (397) found that a variant of CBT called cognitive-behavioral analyses (CBAS) therapy was as effective as nefazodone (mean dose = 460 mg per day) in producing both response and remission in outpatients with moderate to more severe chronic depression. 

A newer class of MAO inhibitors, which has entered clinical practice for the treatment of depression, is known as reversible inhibitors of MAO A (RIMAs). This is a very welcome development in new drug therapeutics for depression, because it has the potential of making MAO A inhibition for the treatment of depression much safer. That is, the suicide inhibitors are associated with the dangerous hypertensive episodes mentioned above, which are caused when patients eat food rich in tyramine (such as cheese). This so-called cheese reaction occurs when the tyramine in the diet releases norepinephrine and other sympathomimetic amines (Fig. 5—23). When MAO is inhibited irreversibly, the levels of these amines rise to a dangerous level... 

It is useful to conceptualize drug treatment of depressive illness as occurring in phases. This approach is based on observations made in the natural course of the disorder and on the knowledge gained during the first decades after the introduction of antidepressant medications. Depression is a chronic, episodic, remitting, and relapsing disease. 

The goal of pharmacological treatment of depression is the resolution of current symptoms and the prevention of further episodes of depression. 

Several of these amines are found in animals and some are involved in nerve transmission see Chapter 27). When plant amines are consumed by animals, they can be quite toxic. For example, phenylethylamine (8) in Acacia berlan-dieri is poisonous to livestock (Smith, 1977b). The presence of amines in foods consumed by humans also has been noted. Catecholamines, indoleamines, and histamine (11) fulfill important metabolic functions, especially in the nervous system and in the control of blood pressure. The occasional presence of greater than usual amounts of tyramine in cheese can cause severe episodes of hypertension, especially in the presence of monoamine oxidase inhibitors, which often are used in the treatment of depression (Smith, 1981). Amines can be formed from bacterial activity in foods (Smith, 1981). 

Treatment of Manic—Depressive Illness. Siace the 1960s, lithium carbonate [10377-37-4] and other lithium salts have represented the standard treatment of mild-to-moderate manic-depressive disorders (175). It is effective ia about 60—80% of all acute manic episodes within one to three weeks of adrninistration. Lithium ions can reduce the frequency of manic or depressive episodes ia bipolar patients providing a mood-stabilising effect. Patients ate maintained on low, stabilising doses of lithium salts indefinitely as a prophylaxis. However, the therapeutic iadex is low, thus requiring monitoring of semm concentration. Adverse effects iaclude tremor, diarrhea, problems with eyes (adaptation to darkness), hypothyroidism, and cardiac problems (bradycardia—tachycardia syndrome). 

Antipsychotic medications are indicated in the treatment of acute and chronic psychotic disorders. These include schizophrenia, schizoaffective disorder, and manic states occurring as part of a bipolar disorder or schizoaffective disorder. The co-adminstration of antipsychotic medication with antidepressants has also been shown to increase the remission rate of severe depressive episodes that are accompanied by psychotic symptoms. Antipsychotic medications are frequently used in the management of agitation associated with delirium, dementia, and toxic effects of both prescribed medications (e.g. L-dopa used in Parkinson s disease) and illicit dtugs (e.g. cocaine, amphetamines, andPCP). They are also indicated in the management of tics that result from Gilles de la Tourette s syndrome, and widely used to control the motor and behavioural manifestations of Huntington s disease. 

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