Positive symptoms

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Initiation of behaviour Mesolimbic pathway to nucleus accumbens from VTA (AIO) Mesocortical pathways to prefrontal cortex from VTA (AIO) Animals Increases locomotor activity and intracranial self-stimulation Humans Hallucinations, psychoses (reward, reinforcement) Animals Decreases activity and self-stimulation Humans Reduces positive symptoms of schizophrenia D2 ... 

The first three characteristics are considered to be the positive symptoms of the disorder. The fourth are described as negative symptoms although they can be divided into true negative symptoms, i.e. diminished emotions and speech and reactive ones, i.e. social apathy and withdrawal brought on by the positive symptoms. Schizophrenics do not have a split personality. Normally their reaction to the positive symptoms is to withdraw quietly but occasionally they will react violently to the voices they hear and shout at them. 

Although there is no evidence that the DA afferents to DLPFC are damaged in schizophrenics, if the cortical pathology does reduce the ability of DA to function there, this would be equivalent to deafferentation and, as in the experimental studies, lead to increased subcortical mesolimbic activity and positive symptoms (Fig. 17.3). Unfortunately there is no good evidence that the nucleus accumbens is more active in schizophrenics or is even the origin of positive symptoms (but see Animal models ). Nevertheless it is a useful working hypothesis. 

A DA antagonist could certainly counter the increased mesolimbic activity and the positive symptoms. On the other hand, they would not be expected to reduce negative symptoms if these arise through an already inadequate DA influence. This fits with clinical experience because most of the neuroleptics are ineffective in treating negative symptoms. In fact if the negative symptoms do result from loss of the actual cortical neurons, rather than input to them, they will be difficult to reverse and much will depend on the precise role of DA in the DLPFC (see later). 

The injection of 6-OHDA into the rat nucleus accumbens produces the expected proliferation of DA receptors and resulting supersensitivity so that doses of apomorphine lower than normal produce a significant attenuation of PPI. This is not seen after the production of supersensitivity by toxin lesions of the substantia nigra and prefrontal cortex. The effects of amphetamine were also mainly modified by accumbens lesions. Thus as DA agonists primarily augment the positive symptoms such findings link these with the accumbens. 

Refractory cases respond to clozapine. If D2 antagonism is considered necessary, or at least desirable, for counteracting positive symptoms it is surprising that a relatively weak D2 antagonist like clozapine should not only be so effective but also prove successful in patients who have not responded to other neuroleptics more potent at D2 receptors. 

Unfortunately although much is known about the pathways and receptors involved in extrapyramidal activity and the mechanism of the EPSs that follow neuroleptic therapy and even the possible origin of negative symptoms in the prefrontal cortex, the precise site of origin and NT involvement in the overriding positive symptoms is less clear. Until that is corrected, permutations of NT antagonisms are likely to multiply with the neuroleptics. 

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens). 

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

For approximately 20% to 30% of people with schizophrenia, drug treatment is ineffective. A standard definition of treatment resistance includes patients who have persistent positive symptoms despite treatment with at least two different antipsychotics given at adequate doses (at least 600 chlorpro-mazine equivalents) for an adequate duration (4 to 6 weeks). In addition, patients must have a moderately severe illness as defined by rating instruments, and have a persistence of illness for at least 5 years.40 These patients are often highly symptomatic and require extensive periods of hospital care. 

Schizophrenia is characterized by three partially independent symptom clusters. These symptom clusters are designated positive symptoms, negative symptoms and cognitive impairments [1], The positive symptoms are the most dramatic and are manifestations of psychosis. 

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. 

One of the most prominent positive symptoms in schizophrenia is the auditory hallucinations that are perceived as distinct voices emanating from outside the individual. Regional cerebral-blood-flow studies in patients experiencing auditory hallucinations reveal activation of the associational auditory cortex during the episodes of hallucinations, but not in their absence. One theory holds that auditory hallucinations occur as a consequence of the inability of individuals with schizophrenia to monitor effectively their inner speech. fMRI studies suggest that... 

Controlled clinical investigations with careful titration of doses in normal subjects demonstrate that ketamine produces negative symptoms, such as withdrawal and the subtle cognitive impairments associated with schizophrenia [25]. As is the case for schizophrenia, these symptoms occur without clouding of consciousness or frank dementia. Positive symptoms with auditory hallucinations and fully... 

Positive symptoms (see Diagnosis section below) may be more closely associated with DA receptor hyperactivity in the mesocaudate, while negative symptoms (see Diagnosis section below) and cognitive symptoms (see Diagnosis section below) may be most closely related to DA receptor hypofunction in the prefrontal cortex. 

Positive symptoms (the ones most affected by antipsychotic drugs) include delusions, disorganized speech (association disturbance), hallucinations, behavior disturbance (disorganized or catatonic), and illusions. 

Clinicians should use standardized psychiatric rating scales to rate response objectively. The four-item Positive Symptom Rating Scale and the Brief Negative Symptom Assessment are scales that are brief enough to be useful in the outpatient setting. 

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