Depression and Schizophrenia

Depression and Schizophrenia

Symptoms of depression occur in a substantial percentage of schizophrenia patients with a wide range of 7 to 75% and a modal rate of 25% and is associated with poor outcome, impaired func-tioning, suffering, higher rates of relapse or rehospitalization, and suicide. It is important to distinguish depression as a symptom or as a syndrome when it occurs. There is an important overlap of symptoms of depression with the negative symptoms. Differen-tiating these states can sometimes be difficult especially in pa-tients who lack the interpersonal communication skills to articu-late their internal subjective states well. A link between typical antipsychotic use and depression has been suggested with some considering depression to be a form of medication induced aki-nesia. Many patients have a reaction of disappointment, a sense of loss or powerlessness, or awareness of psychotic symptoms or psychological deficits that contributes to depression. Depression in schizophrenia is heterogeneous and requires careful diagnostic clarification. DSM-IV suggests that the term “postpsychotic de-pression” be used to describe depression that occurs at any time after a psychotic episode of schizophrenia, even after a prolonged interval. The atypical antipsychotic medications, with less po-tential to cause motor side effects and different mechanisms of action at receptor levels, themselves may contribute substantially towards a decrease in the rate of depression. Moreover, the atypi-cal antipsychotic medications appear to be superior to standard neuroleptics in treatment of negative symptoms. The clear advan-tage of atypical antipsychotic medications over the typical ones in treatment of psychosis itself can possibly further decrease the rate of depression. The impact of clozapine on the rate of suicide is significantly superior compared with the conventional agents. However, a large number of patients still end up with a depression that will require treatment with an antidepressant.

Risks and Side Effects of Typical Neuroleptics

Extrapyramidal symptoms are side effects of typical antipsy-chotic medications that include dystonias, oculogyric crisis, pseudoparkinsonism, akinesia and akathisia. They are referred to collectively as extrapyramidal symptoms or EPS because they are mediated at least in part by dopaminergic transmission in the extrapyramidal system. Prevalence rates vary among the differ-ent types of extrapyramidal symptoms. When present, they can be uncomfortable for the patient and a reason for noncompliance.

Dystonias are involuntary muscular spasms that can be brief or sustained, involving any muscle group. They can occur with even a single dose of medication. When they develop sud-denly, these spasms can be quite frightening to the patient and potentially dangerous, as in the case of laryngeal dystonias. They are more likely to be seen in young patients. Pseudoparkinsonism and akinesia are characterized by muscular rigidity, tremor and bradykinesia, much as in Parkinson’s disease. On examination patients typically have masked facies, cogwheel rigidity, slowing and decreased arm swing with a shuffling gait. This condition is reported to be more prevalent than the dystonias, presenting with a frequency ranging from 15%.

Akathisia is more common, affecting more than 20% of patients taking neuroleptic medications (Ayd, 1961; Marsden et al., 1986). This clinical entity presents as motor restlessness or an internal sense of restlessness. Often patients experiencing akathisia are unable to sit still during an interview. Akathisia is difficult to differentiate from agitation. The tendency to treat agi-tation with neuroleptics may exacerbate akathisia, making treat-ment decisions challenging.

Treatment of EPS can be difficult but usually involves administration of anticholinergic medications. Some advocate the use of prophylactic anticholinergic agents when beginning typical neuroleptic treatment to decrease the incidence of EPS. This option may be appropriate, but it should be used with cau-tion, considering the side effects associated with anticholinergic agents and their potential for abuse. Treatment of acute dystonic reactions usually involves acute intramuscular administration of either an anticholinergic or diphenhydramine. Akathisia may not respond to anticholinergic medications. Both neuroleptic dosage reduction and the use of beta-blocking agents such as propranolol have been found to be efficacious in the treatment of akathisia.

Nonextrapyramidal side effects of the typical antipsy-chotic agents include those that are secondary to blockade of muscarinic, histaminic and alpha-adrenergic receptors. These side effects, which are more commonly seen with the low-po-tency neuroleptics, include sedation, tachycardia and anticholin-ergic side effects such as urinary hesitancy or retention, blurred vision, or constipation. Other nonextrapyramidal side effects include some cardiac conduction disturbances, retinal changes, sexual dysfunction, weight gain, lowered seizure threshold and a risk of agranulocytosis.

Neuroleptic malignant syndrome (NMS) is a relatively rare but serious phenomenon seen in approximately 1% of patients taking neuroleptics. It can be fatal in 15% of cases if not prop-erly recognized and treated. Because the symptoms of NMS may reflect multiple etiologies, making diagnosis difficult, Levenson (1985) has proposed clinical guidelines. According to Levenson, three major or two major and four minor manifestations are in-dicative of a high probability of NMS. Major manifestations of NMS comprise fever, rigidity, and increased creatine kinase levels, and minor manifestations include tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis and leukocytosis. Others do not subscribe to the major–minor manifestation distinctions. In general, NMS is considered to be a constellation of symptoms that usually develops during 1 to 3 days. Although its pathogenesis is poorly understood, it has been associated with all antidopaminergic neuroleptic agents and presents at any time during treatment. It must be distinguished from other clinical entities, including lethal catatonia and malig-nant hyperthermia.

The mainstay of treatment is cessation of neuroleptic treat-ment and supportive care, including intravenous hydration, re-versal of fever with antipyretics and cooling blankets, and care-ful monitoring of vital signs because of the risk of cardiac andrespiratory disturbance. Rhabdomyolysis is one of the most seri-ous sequelae of NMS; it can lead to renal failure unless patients are well hydrated. In some cases, dantrolene and bromocriptine have been reported to be effective pharmacological treatments. Though quite rare, NMS has been reported even with the use of novel an-tipsychotic agents. The decision to rechallenge the patient with neuroleptics after an episode of NMS must be made with caution.

One of the major risks of neuroleptic treatment with the traditional antipsychotic agents is that of tardive dyskinesia, a potentially irreversible syndrome of involuntary choreoathetoid movements and chronic dystonias associated with long-term neu-roleptic exposure. These buccal, orofacial, truncal, or limb move-ments can be exacerbated by anxiety and disappear during sleep. They can present with a range of severity, from subtle tongue movements to truncal twisting and pelvic thrusting movements and even possible respiratory dyskinesias. The prevalence rates for this syndrome range from less than 10 to more than 50%), but it is generally accepted that the risk increases 3 to 5% per year for each year the patient is treated with typical neuroleptics. Older age is a considerable risk factor for tardive dyskinesia, and there is some evidence that women are at increased risk for the development of this condition. Of note, a withdrawal dyskinesia that resembles tardive dyskinesia may appear on cessation of the neuroleptic. The specific mechanism involved in tardive dyski-nesia remains unclear, although supersensitivity of dopaminergic receptors has been implicated.

All patients receiving traditional neuroleptic treatment should be monitored regularly for any signs of a movement dis-order. DSM-IV now includes a diagnosis of neuroleptic-induced tardive dyskinesia. If tardive dyskinesia is suspected, the benefits of antipsychotic treatment must be carefully weighed against the risk of tardive dyskinesia. This should be discussed with the pa-tient, and the antipsychotic should be removed if clinically feasi-ble or at least maintained at the lowest possible dose that provides antipsychotic effect. This would also be an indication to switch to the novel antipsychotic agents with significantly reduced risk of TD or in the case of clozapine no risk of TD. In many instances, clozapine (and possibly quetiapine or olanzapine) may be the best treatment that can be offered for the TD itself. Unfortunately, there is no specific treatment of tardive dyskinesia, although some investigators have proposed the use of adrenergic agents such as clonidine, calcium channel blockers, vitamin E, benzodiazepines, valproic acid, or reserpine to reduce the spontaneous movements.

Sudden death in psychiatric patients treated with typical antipsychotic drugs has been reported for a long time. Sudden cardiac deaths probably occur from prolongation of the ventricu-lar action potential duration represented as the QT interval (or QTc when corrected for heart rate) on the electrocardiogram resulting in a polymorphic ventricular tachycardia termed tor-sades de pointes that can degenerate into ventricular fibrilla-tion. The incidence of torsades de pointes is unknown and the specific duration of the QTc interval at which the risk of an ad-verse cardiac event is greatest has not been established. QTc pro-longation alone does not appear to explain torsades de pointes; several other risk factors must be present simultaneously with QT prolongation before torsades de pointes occur. These risk factors may include hypokalemia, hypomagnesemia, hypocal-cemia, bradycardia, preexisting cardiac diseases (life-threaten-ing arrhythmias, cardiac hypertrophy, heart failure and congeni-tal QT syndrome), female gender, advancing age, baseline QTc interval of more than 460 m/sec and a long list of medications. In some instances, torsades de pointes may be associated with anincrease in drug plasma concentrations (e.g., combination with drugs that inhibit the cytochrome P450 systems). Thus, the in-crease in polypharmacy in psychiatry is especially of concern. The frequency of ECG abnormalities in patients treated with an-tipsychotic drugs is unclear QTc prolongation has been reported with virtually all antipsychotic drugs. QTc prolongation by more than two standard deviations was reported in 8% of psychiatric patients treated with antipsychotics and especially in those re-ceiving thioridazine (Riley et al., 2000; 2001). Of the typical an-tipsychotic drugs, haloperidol, chlorpromazine, trifluoperazine, mesoridazine, prochlorperazine, droperidol and fluphenazine have all been reported to cause QTc prolongation and torsades de pointes, but thioridazine may be the worst offender. Pimozide, another typical antipsychotic, has also been associated with QTc prolongation, torsades de pointes and deaths. A reevaluation by the FDA of the cardiac safety parameters of thioridazine, me-soridazine and droperidol resulted in a black box warning due to significant QTc prolongation. Thus, it is important to monitor QTc interval in the high-risk population to prevent this rare, but potentially fatal side effect.