Bipolar disorder positive symptoms

The positive symptoms are the most responsive to antipsychotic medications, such as chlorpromazine or halo-peridol. Initially, these drugs were thought to be specific for schizophrenia. However, psychosis is not unique to schizophrenia, and frequently occurs in bipolar disorder and in severe major depressive disorder in which paranoid delusions and auditory hallucinations are not uncommon (see Ch. 55). Furthermore, in spite of early hopes based on the efficacy of antipsychotic drugs in treating the positive symptoms, few patients are restored to their previous level of function with the typical antipsychotic medications [2]. 

The typical antipsychotic drugs, which for 50 years have been the mainstay of treatment of schizophrenia, as well as of psychosis that occurs secondary to bipolar disorder and major depressive disorder, affect primarily the positive symptoms[10]. The behavioral symptoms, such as agitation or profound withdrawal, that accompany psychosis, respond to the antipsychotic drugs within a period of hours to days after the initiation of treatment. The cognitive aspects of psychosis, such as the delusions and hallucinations, however, tend to resolve more slowly. In fact, for many patients the hallucinations and delusions may persist but lose their emotional salience and intrusiveness. The positive symptoms tend to wax and wane over time, are exacerbated by stress, and generally become less prominent as the patient becomes older. 

Olanzapine (Zyprexa). The olanzapine molecule is structurally very similar to clozapine and therefore exerts very similar effects on brain receptors. The dose range of olanzapine for treating schizophrenia is from 5 to 30mg/day. Like clozapine, olanzapine appears to treat both positive and negative symptoms. It is also approved for the treatment of the manic phase of bipolar disorder. It has also been shown to augment the antidepressant effects of fluoxetine in refractory patients. 

Nonpsychotic persons also experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. The ability of the atypical antipsychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by typical agents. 

For approximately 70% of patients with schizophrenia, and probably for a similar proportion of patients with bipolar disorder with psychotic features, typical and atypical antipsychotic drugs are of equal efficacy for treating positive symptoms. However, the evidence favors atypical drugs for benefit for negative symptoms and cognition, for diminished risk of tardivedyskinesia and other forms of EPS, and for lesser increases in prolactin levels. 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

Aripiprazole Blockade of 5HT2A receptors > blockade of D2 receptors Some a blockade (clozapine, risperidone, ziprasidone) and M-receptor blockade (clozapine, olanzapine) variable receptor blockade (all) Schizophrenia—improve both positive and negative symptoms bipolar disorder (olanzapine or risperidone adjunctive with lithium) agitation in Alzheimer s and Parkinson s (low doses) major depression (aripiprazole) Toxicity Agranulocytosis (clozapine), diabetes (clozapine, olanzapine), hypercholesterolemia (clozapine, olanzapine), hyperprolactinemia (risperidone), QT prolongation (ziprasidone), weight gain (clozapine, olanzapine)... 

Disorders in addition to schizophrenia that can have positive symptoms include bipolar disorder, schizoaffective disorder, psychotic depression, Alzheimer s disease... 

Although the usefulness of the atypical antipsychotics is best documented for the positive symptoms of schizophrenia, numerous studies are documenting the utility of these agents for the treatment of positive symptoms associated with several other disorders (discussed in Chapter 10 see Fig. 10—2). Atypical antipsychotics have become first-line acute and maintenance treatments for positive symptoms of psychosis, not only in schizophrenia but also in the acute manic and mixed manic-depressed phases of bipolar disorder in depressive psychosis and schizoaffective disorder in psychosis associated with behavioral disturbances in cognitive disorders such as Alzheimer s disease, Parkinson s disease, and other organic psychoses and in psychotic disorders in children and adolescents (Fig. 11—52, first-line treatments). In fact, current treatment standards have evolved in many countries so that atypical antipsychotics have largely replaced conventional antipsychotics for the treatment of positive psychotic symptoms except in a few specific clinical situations. 

Profound mood-stabilizing effects of the atypical antipsychotic drugs were observed once their antipsychotic effects were documented. These effects on mood appear to be quite independent of their effects on positive symptoms of psychosis. The most dramatic story may be how impressive the atypical antipsychotics are turning out to be for the treatment of bipolar disorder (Fig. 11 — 53). Although the best documented effect of these drugs is to reduce psychotic symptoms in the acute manic phase of bipolar disorder, it is clear that these agents also stabilize mood and can help in some of the most difficult cases, such as those marked by rapid cycling and mixed simultaneous manic-depressed states that are often nonresponsive to mood... 

FIGURE 11-52. Positive symptom pharmacy. First-line treatment of positive symptoms is now atypical antipsychotics (SDA), not only for schizophrenia but also for positive symptoms associated with bipolar disorder, Alzheimer s disease, childhood psychoses, and other psychotic disorders. However, conventional antipsychotics (D2) and benzodiazepines (BZ) are still useful for acute intramuscular administration (in case of emergency), and D2 for monthly depot injections for noncompliant patients, as well as for second-line use after several atypical agents fail. Clozapine (C), polypharmacy, and combinations (combos) are relegated to second- and third-line treatment for positive symptoms of psychosis. 

Predictors of a positive response with valproate include rapid cycling, mixed episodes, comorbid panic disorder, organic mental disorders (e.g., head trauma), and mental retardation. " Low-dose valproate (125 to 500 mg/day) has been reported to be effective in reducing mood cycling in bipolar II disorder and cyclothymia. Oral loading with divalproex sodium, 20 mg/kg per day, may produce a rapid reduction in manic and psychotic symptoms within 4 days without causing major side effects, although there may be a lag time to obtain full antimanic efficacy. Development of tolerance and loss of efficacy with valproate occurs in some patients after several years of treatment." ... 

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