Negative symptoms, of schizophrenia

The prefrontal cortex (PFQ and in particular the dorsal lateral part (DLPFQ appear to be particularly important in schizophrenia (Kerwin 1992). Lesions there are known to produce functional defects in humans reminiscent of many of the negative symptoms of schizophrenia, such as attention and cognitive defects and withdrawal. Despite this, no specific pathology is seen in the DLPFC in schizophrenics although there is some atrophy and neuronal loss which are normally old and could be congenital. That being so, it is necessary to explain why the symptoms become apparent only in adolescence. 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

D-cycloserine An amino acid analogue of D-serine that has been reported to show benefits in treating the negative symptoms of schizophrenia. 

Despite their importance in psychiatry, the neuroleptics are by no means cure-alls. Even patients that respond extremely well to neuroleptics remain disturbed. Specifically, though their florid hallucinations and delusions, the positive symptoms of schizophrenia, are alleviated, patients remain emotionally detached from the environment. This wallflower syndrome and related symptoms are commonly designated the negative symptoms of schizophrenia and often are the most disabling ones. The first glimmer of effective treatment of such negative symptoms came with the drug clozapine. 

There are data to confirm and reject the association of the Cys23Ser S-HT and the Gly22Ser 5-HTj receptor variants, characterized in vitro by reduced agonist potency, with phenotypes such as intractable suicidal ideation (98), ADHD (100), alcohol dependence, and schizophrenia (98,99,109-116). While the -1348 A/G polymorphism of the S-HT receptor has been associated with the negative symptoms of schizophrenia, other studies of eating disorders appear to be equivocal. A body of evidence is available, however, that S-HT variants may be associated with psychotic symptoms in Alzheimer s patients (94,100,117,118). 

Hamdani, N., Bonniere, M., Ades, J., Hamon, M., Boni, C., and Gorwood, P. (2005) Negative symptoms of schizophrenia could explain discrepant data on the association between the 5-HT2A receptor gene and response to antipsychotics. Neurosci. Lett. 377,69-74. 

Deiusionai Disorder. Patients with delnsional disorder share the presence of delusions with schizophrenia patients. However, the delnsions are not bizarre as they often are in schizophrenia. Patients with delnsional disorder often fnnction fairly well in society. They can nsnally hold employment and typically remain active members of their families. Delnsional disorder patients do not have the negative symptoms of schizophrenia, do not experience hallncinations, and do not suffer from the gross social impairment of schizophrenia. They may, however, have circumscribed social problems that are directly related to the content of their delusions. The delusions often are believable or at least somewhat plausible. 

In contrast, it is often hypothesized that the negative symptoms of schizophrenia are a result of decreased activity of the mesocortical dopamine pathway. Unfortunately, dopamine blocking by typical antipsychotics in the mesocortical pathway does not improve the negative symptoms, and may even worsen them. 

Quetiapine (Seroquel). Quetiapine is the fourth of the atypical antipsychotics introduced in the United States. It is effective in both positive and negative symptoms of schizophrenia within a dose range of 150 to 750mg/day in two divided... 

Other research has studied how childhood experiences may contribute to the development of a Cluster A personality disorder. Psychosocial explanations revolve around the observation that there is a degree to which distrust is a rational response to certain experiences. Some have theorized that cold and indifferent parenting can contribute to the disinterest in relationships that characterizes Cluster A disorders. It is in fact likely that a genetic predisposition to subclinical personality traits that mirror the positive and/or negative symptoms of schizophrenia may combine with certain developmental experiences that conspire to the development of a Cluster A personality disorder. 

Schizoid Personaiity Disorder (SPD). Again, there is very little research to guide in the selection of medications to treat the schizoid patient. If we conceptualize the symptoms of SPD as most resembling the negative symptoms of schizophrenia, the choice of agents would tend to favor the atypical antipsychotic drugs as opposed to the older typical antipsychotics. Consequently, we also recommend low doses of an atypical antipsychotic as a first-line treatment for SPD. 

Schizotypai Personaiity Disorder (STPD). Patients with STPD most closely resemble those with schizophrenia. They have parallels to both the positive and negative symptoms of schizophrenia. Of the three Cluster A personality disorders, most medication research has been conducted in STPD though it is also quite limited. 

Parkinsonism. As will be discussed later, dopamine-blocking antipsychotics and rarely other psychotropic medications can produce symptoms that resemble Parkinson s disease. This includes an expressionless face, slowed movement, and a stooped posture. In many respects, medication-induced parkinsonism resembles both depression and the negative symptoms of schizophrenia. Again, one must decide if it is the illness or the medication. Do you decrease the medication to remedy the side effect Or do you increase the medication to treat the illness, anticipating that a higher dose may prove more beneficial (though this is not always what is found) ... 

In this case, a more careful psychiatric and physical examination can be of help. Although there are admitted similarities to depression and the negative symptoms of schizophrenia, Parkinson s disease is also associated with a resting tremor, called cogwheel rigidity, and at times drooling. These other symptoms are not typically due to psychiatric illness. If these symptoms are present, one should investigate the possibility of a medication side effect or the presence of Parkinson s disease. 

Other hallucinogenic drugs including substances related to LSD are mentioned under delirium. Phencyclidine and ketamine can also produce similar hallucinatory states without delirium including time distortion, distortion of body image, synaesthesia, visual hallucinations, depersonalisation, derealisation, paranoid ideation and a schizophreniform psychosis which includes the negative symptoms of schizophrenia (Gorelick Balster, 1995). 

Limited clinical experience, but similar to clozapine and risperidone maybe effective for negative symptoms of schizophrenia so far no agranulocytosis reported with quetiapine... 

Unlabeled Uses Treatment of Alzheimer s disease, attention-deficit-hyperactivity disorder, depression, early Parkinson s disease, extrapyramidal symptoms, negative symptoms of schizophrenia... 

Heresco-Levy, U., Javitt, D.C., Ermilov, M., Mordel, C., Silipo, G., and Lichtenstein, M. (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56 19-36. 

Several clinical trials with adults have demonstrated that amisulpride is effective in improving positive and negative symptoms of schizophrenia (Moller, 2000). There is one clinical trial including adolescent and young adulthood schizophrenia (Paillere-Martinot, 1995). Amisulpride was generally well tolerated and improved both positive and negative symptoms. 

Underactivity of dopamine in mesocortical pathways, specifically those projecting to the frontal lobes, may account for the negative symptoms of schizophrenia (e.g., anergia, apathy, lack of spontaneity) (Davis et al. 1991 Goff and Evins 1998). In addition, this underactivity in the frontal lobes may serve to disinhibit mesolimbic dopamine activity via a corticolimbic feedback loop. Overactivity of mesolimbic dopamine is the result, which manifests as the positive symptoms of schizophrenia (e.g., hallucinations, delusions). 

Another hypothesis (Crow, 1982) involves a division of schizophrenias into two types Type I corresponds to acute schizophrenia or schizophreniform disorder in which one observes more positive symptoms of hallucinations and delusions with a good prognosis and excellent response to neuroleptics... Type II represents chronic schizophrenia with affective flattening, poverty of speech and loss of drive, the so-called negative symptoms of schizophrenia. Type II patients respond less well to neuroleptics... (Snyder, 1982). Type I patients would fit into the dopamine hypothesis whereas a pathophysiological basis other than dopaminergic hyperactivity must be assumed for type II patients. However, as pointed out by Snyder (1982). "one should be cautious about drawing such a distinction. ... 

Each is effective in alleviating positive and negative symptoms, particularly drug-induced secondary negative symptoms of schizophrenia. 

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