Drug –Specific Responsiveness of Negative Symptoms


Saeed Shoja Shafti (MD)
Assistant professor of psychiatry University of social welfare and
Rehabilitation sciences (USWR)
TEHRAN – IRAN

Shahre Rey
Amin Abad
Razi Psychiatric Hospital
Department of Psychiatry

 

Abstract
Introduction: negative symptoms in schizophrenia are among the important barriers against psychosocial rehabilitation of such patients. Adjunctive drugs can be used for reducing the severity of these symptoms. In this research we studied the specific efficacy of different cluster of drugs on negative symptoms to see that whether there is any relationship between symptom's responsiveness and drug's variety.

Materials and method: after a primary prevalence survey regarding Negative symptoms, 170 schizophrenic patients were divided into three different groups, and then the aforesaid adjuvant drugs were examined in three double-blind clinical controlled trials. Estimation of negative symptoms by “SANS” were done at the beginning of each trial for the first time and then three weeks later, after prescription of drugs in lower dosage and finally at the end of sixth week, means three weeks after doubling the dosages. The data were analyzed by z and chi-square (X2-test) formula.

Results: Attention Deficit was the most responsive symptom in comparing with other negative ones. Nortriptyline, Fluexetine and Bromocriptine had ameliorated it in 40%, 41.6% and 24% of the patients in their own groups, respectively. The best effect of Clomipramine, Fluvoxamine,and Citalopram was on Affective Blunting ,which showed amelioration in 40%,50% and 50% of the patients, treated by the aforesaid drugs ,respectively. All of them are grouped as Serotonoin Reuptake Inhibitors .Maprotiline (a noradrenergic tetracyclic) had reduced the severity of Alogia and Anhedonia-asociality in 50% of cases in its group, which was remarkably more than other negative symptoms in the same group. The best effect of Alprazolam (as a benzodiazepine) was on Avolition-Apathy (40%).

Conclusion: Different adjunctive drugs had different profile of benefit on negative symptoms in schizophrenia. This phenomenon can guide the therapist towards a better and more effective amelioration of such symptoms, which need to be overcome in a rehabilitation goal setting process.

Introduction
Negative symptoms in schizophrenia as one of the major criteria in addition to other ones in DSM TV-TR, include  presentations as follows: 1)Restricted up to flat affect 2)Apathy 3)Alogia 4)Anhedonia 5)Avolition 6)Asociality 7)Attention Deficit (1,2 ). According to Carpenter existence of at least two of these symptoms or more for duration not less than twelve month is enough for diagnosis of deficit syndrome, as a subtype of schizophrenia (3). In DSM IV-IR, too, negative symptoms in addition to one of the positive symptoms (delusion, hallucination, disorganized speech, and disorganized behavior) for duration of at least one month is enough for diagnosis of acute phase. Anxiety, suspiciousness, mental retardation, depression, Parkinsonism and lack of environmental stimulants can result in secondary negative symptoms or reinforcement of primary ones. The importance of negative symptoms can be deduced also from the hidden firm barrier which is constructed by them between patients and others around them. Inaccessibility to patients which is resulted from such cluster of symptoms, after suppression of positive symptoms, can make different psychosocial interventions, which are employed in the framework of community psychiatry, futile. Adjunctive pharmacotherapy can reduce the severity of such symptoms in a variety of ways. Different drugs like Heterocyclics , Serotonin-Reuptake Inhibitors and Dopaminergic ones, have different profile of benefit on these symptoms .This variety of profit deserves an appropriate amount of attention because it can prevent unnecessary pharmacokinetic interactions or side effects due to  application of more beneficial ones. Although the existing data are not enough yet to guide us towards a comprehensive formulation of these relationship but nevertheless it remains its clinical importance and looking for further findings in the future. As a preliminary investigation for portraying the problem of negative symptoms among our schizophrenic patients and its amplitude we did a prevalence survey on a sample of our patients and then applied the different cluster of adjunctive drugs on some of them.

Methods and Materials
70 patients with diagnosis of schizophrenia (according to the DSM IV-TR criteria) had been chosen randomly in Razi Psychiatric Hospital in summer of 2003, for a survey regarding to the prevalence of negative symptoms and their severity. In this regard some of the patients had been excluded due to some intervening factors (table 1). This cluster of symptoms had been estimated and scored by Scale for Assessment of Negative Symptoms (SANS) (4). After determining this prevalence, they had been divided to three different groups. Group A (n=40) for a Clinical Controlled Trial (CCT) regarding the effectiveness of Clomipramine, Alprazolam, and Citalopram on reducing the severity of negative symptoms

 
Table 1- Inclusion and Exclusion criteria

Inclusion criteria	Exclusion criteria
Schizophrenia	1-Depression 2-Schizoaffective 3-Mental retardation 4-Bipolar disorders 5-Neurological disorders 6-Using atypical antipsychotic 7-Using antidepressants or lithium 8-Medical complications 9-Unstable, irritable, aggressive patients 10-Duration less than one year 11-Parkinsonism 12-Medical deafness or muteness

 

Groups B (n=100) with a similar approach with respect to the moderating effect of Bromocriptine, Fluoxetine and Nortriptyline, and finally group C (n=30) regarding similar effects of Fluvoxamine and Maprotiline. In every group and at the beginning of the related trials, before addition any adjunctive drug, a new estimation of the negative symptoms by SANS had been performed as the baseline and then the adjunctive drugs had been added to the patient's current treatments, including typical antipsychotics (one of the Chlorpromazine, haloperidol, Perphenazine, Trifluperazine or Fluphenazine decanoate). Each drug in each group was started with its lower dose and then at the end of the third week after beginning adjunctive treatments, again another estimating of negative symptoms by SANS had been performed. Then the dosage of the aforesaid drugs had been doubled and after another three weeks the final severity of negative symptoms and their changing had been registered. Generally grade 1, 2 and 3 were regarded as non-severe (mild) symptoms and grade 4 and 5 as severe. At the end, data had been analyzed by Z  and chi-square (X2-test) formula. All of the controlled trials had been done in a double-blind fashion and by the same team.
Interview with the patients and their relatives, and also observations and remarks put forwarded by their nurses, social workers, psychologists and occupational therapists had provided the necessary resources for this research.

Results: the prevalence of negative symptoms among schizophrenic patients was remarkable. Almost no patient was free from negative symptom, and no specific or similar pattern could be found among them. Although some of the patients had similar severity in all of their negative symptoms, but many of them had discrete symptoms with different severity. The prevalence of Affecting Blunting, Alogia, Avolition-Apathy, Anhedonia-Asociality and finally Attention Deficit among this sample (n=270) were: %96/28 (n=260), %94/80 (n=156), %99.62 (n=269), %98.88 (n=267) and %99.25 (n=268) respectively

Severity Negative Symptoms	Normal		Mild Grade 1,2,3 SANS		Severe Grade 4 , 5 SANS
Affective Blunting	10	%3.72	160	%59.25	100	%37.03
Alogia	14	%5.20	155	%57.40	101	%37.40
Avolition-Apathy	1	%0.38	171	%63.33	98	%36.29
Anhedonia-Isolation	3	%1.12	144	%53.33	123	%45.55
Attention Deficit	2	%0.75	115	%42.59	153	%56.66

(Table 2). The age of these patients were between 24-68 years (mean=43.6) and the duration of their residency in hospital was between 2.5-28 years (mean=17.83) and all of them were male. Then we selected forty (40) patients among them, as group A, for performing the first trial with Citalopram, Alpazolam Clomipramine and placebo, after dividing them into four subgroup, with every subgroup containing ten (10) patients. The starting dose was 20mg, 0/75 mg, and 25 my respectively for Citalopram, Alprazolam and Clomipramine which were doubled after three weeks. The whole of trial had been done according to the aforesaid processes in method and material’s section. According to the resulted data, Citalopram (p<0/001), Alprazolam (p<0/01) and Clomipramine (p<0/01) were more effective than placebo in reducing the severity of negative symptoms. This different was not large between them themselves (p<0.25). Generally this reduction in severity was restricted to 20% from baseline, and only in Clomipramine group 40% reduction was seen in Alogia and Attention Deficit in two separate patients respectively. There was not any relation between response to adjunctive drugs and the severity.

 

Table 3- Improvement of Negative symptoms by adjunctive drugs in schizophrenic patients.

Negative   Symptoms   Drugs	Affecting Blunting		Alogia		Avolition Apathy		Anhedonia Asociality		Attention Deficit		Total
	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent
Citalopram 20-40 mg	5	50%	4	40%	4	40%	3	30%	4	40%	20	80%
Alprazolam 0.75-1.5 mg	3	30%	3	30%	4	4%	2	20%	2	20%	14	50%
Clomipramine 25-50 mg	4	40%	2	20%	1	10%	3	30%	3	30%	13	50%
Placebo	0	0%	0	0%	0	0%	0	0%	0	0%	0	0%

In second trial we selected another one hundred (100) patients and divided them into four subgroups (25 cases in each subgroup). Here we started Bromocripme, Fluoxetine, and Nortiptyline with dosage, of 2.5 mg, 20 mg and 25 mg respectively for the first three subgroups and placebo for the last subgroup. One patient in the Fluoxetine subgroup, due to his inclination and one in the placebo subgroup due to cardiac infarction were omitted from this trial. After three weeks the aforesaid dosages doubled and the adjuvants prescribed for another three weeks before trial's termination. 37.5% (n-9), 44% (n=11), 62.5% (n=15), and 8% (n=20) of patients in subgroups showed 20% reduction in the severity of some of their negative symptoms under the influence of placebo, Bromocriptine, Fluoxetine and Nortriptyline respectively. Only in three patients in the Nortiptyline subgroup and one patient in the Bromocriptine subgroup there was shown 40% improvement of their negative symptoms. Generally these reductions were taken place discretely among five clusters of such symptoms. There was no difference between mild or severe symptoms regarding their response to the adjunctive drugs.

Table 4 - Improvement of Negative symptoms by adjunctive drugs in schizophrenia patients.

Negative            Symptoms Drugs	Affecting Blunting		Alogia		Avolition Apathy		Anhedonia Asociality		Attention Deficit		Total
	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent	No of patient	Percent
Bromocriptine 2.5-5 mg	3	12%	5	20%	3	12%	3	12%	6	24%	20	44%
Fluoxetine 20-40 mg	4	16.6%	4	16.6%	7	29.1%	2	8.3%	10	41.6%	27	62.5%
Nortriptyline 25-50 mg	6	24%	9	36%	8	32%	9	36%	10	40%	42	80%
Placebo	2	8.3%	6	25%	1	4.1%	4	16.6%	6	25%	19	37.5%

In the third trial, another thirty (30) patients were divided into three subgroups (included 10 cases in each subgroup) and 25 mg Maprotiline, 50 mg Fluvoxamine, and placebo were added as adjunctive drugs to their current antipsychotic drugs respectively. After three weeks these dosages doubled and maintained for another three weeks, before ending the trial. %80 (n=8) 60% (n=6), and 20% (n=2) of patients showed 20% improvement in some of their negative symptoms under the influence of Maprotiline, Fluvoxamine and placebo respectively. (Table 5). This effect was remarkable for Maprotiline in comparing with placebo (p<0/01), and it was greater for Fluvoxamine too (p<0/1).

Table 5 - Improvement of Negative Symptoms by Adjunctive Drugs in Schizophrenia Patients.

Improved                Negative               Symptoms   Drugs	Affective Blunting		Alogia		Avolition Apathy		Anhedonia Asociality		Attention Deficit		Total
	No of patients	Present %	No of patients	Percent %	No of patients	Percent %	No of patients	Percent %	No of patients	Percent	No of patients	Percent %
Maprotiline 25-50 mg	3	30%	5	50%	0	0%	5	50%	3	30%		80%
Fluvoxamine 50-100 mg	5	50%	3	30%	1	10%	3	30%	1	10%		60%
Placebo	0	0%	2	20%	0	0%	1	10%	0	0%		20%

 

In this sample severe symptoms responded more than mild ones to adjunctive drugs and in %79.41 of cases this improvement was started with higher dosages. There was not any patient with improvement in all of his Negative symptoms, and generally these reductions had been taken place discretely, like the previous trials (Table 5). 

Generally in these trials, Attention Deficit was the most responsive symptom (31.2%, n=39:125) and Avolition-Apathy the least responsive one (22.4%, n=28:125) (Table 6).Also Maprotiline was remarkably more effective than Bromocriptine  (P< 0.05 ) and Fluoxetine (P<0.01) in amelioration of Anhedonia-Asociality and  Alprazolam and Citalopram were distinctively more beneficial than Maprotiline  in reducing the severity of Avolition-Apathy (P<0.025) .On the other side ,Affective Blunting was more responsive to Fluvoxamine and Citalopram   in comparison with Bromocriptine (P<0.025) or Fluoxetine(P<0.05).In addition , Maprotiline  was more effective on Alogia and Anhedonia in its subgroup than Avolition-Apathy(P<0.025).

Table 6. Individual and General Response of Negative Sumptoms to Adjunctive Drugs.

Drug Symptom	Bromocriptine	Alprazolam	Clomipramine	Maprotiline	Nortriptyline	Fluoxetine	Fluvoxamine	Citalopram	Total
Affective Blunting	12%	30%	40%	30%	24%	16.6%	50%	50%	26.4%
Alogia	20%	30%	20%	50%	36%	16.6%	30%	40%	28%
Avolition Apathy	12%	40%	10%	0%	32%	29.1%	10%	40%	22.4%
Anhedonia Asociality	12%	20%	30%	50%	36%	8.3%	30%	30%	24%
Attention Deficit	24%	20%	30%	30%	40%	41.6%	10%	40%	31.2%

 

Discussion
Effectiveness of adjunctive drugs in reducing the severity of Negative symptoms is interesting. Although the positive effects of Clomipramine had been reported by LindenMayer (1990-1993), but there was not any description regarding its specificity or else on each negative symptom individually, except than general increase in function and also reduction of obsessive symptoms in treated patients. Regarding Bromocriptine, too, there was some positive amelioration in anergia, accoding to Brief Psychiatric Rating Scale (BPRS), reported by Wolf (1992) and Leviminzi (1991) (5). Also there is some evidence that Amisulpride (a standard antipsychotic) can ameliorate to some degree Apathy, lack of spontaneity and Affective Blunting in some patients (5).Clozapine and Olanzapine too, as atypical antipsychotics, have been reported to have positive effects on Negative symptoms in schizophrenic patients. But their profit, too, is not unlimited. The major benefit of Clozapine had been on Anergia (Kane, 1988) and also on Alogia and Anhedonia (Picker, 1992) (6).The first trial had been scored by BPRS and the second one by SANS. But regarding Olanzapine, according to an important controlled study on 325 schizophrenic patients, which was comparing its effect with Haloperidol and placebo, there was positive effect peculiarly on Affective Blunting and Avolition-Apathy. But its effect on Anhedonia-Asociality was not remarkable in this regard. The mean dosage of Olanzapine in the aforesaid study was 15mg daily (Tollefson, 1997) (7).

  In our trials there was some relationship between some kind of negative symptoms and their better reponse to different adjunmctive drugs. For example Affective Blunting had been ameliorated mainly by Serotonin Reuptake Inhibitors, like Clomipramine, Fluvoxamine and Citalopram in 40%, 50% and 50% of their samples respectively. Or as another example, Attention Deficit had been influenced mainly by Nortriptyline, Fluoxetine and Bromocriptine in 40%, 41.6% and 24% of the patients respectively. As is known these drugs belong to different classes with different pharmacodynamic properties.But such a response were weakest for Fluvoxamine. Meanwhile in this regard the most benefit of Maprotiline, a tetracyclic with mainly noradrenergic characteristics, was on Alogia and Anhedonia –Asociality, which was evident in 50% of the patients in the related subgroup. The most profit of Alprazolam (as a Benzodiazepine), too, was on Avolition-Apathy, which had not responded at all to Maprotiline and also had showed a weak response to Bromocriptine, Clomipramine and Fluvoxamine. Therefore in addition to the current standpoint that says that schizophrenia is not a single illness but rather  a heterogenic entity  with different physiopathologic  causes  and  morbid expressions, it seems that this point of view may pertain to its symptoms too, and especially with regard to negative symptoms ,their variety of response may result from different involvement of neuronal pathways and dependent  neurotransmissions , which leads to a variety of interpersonal disturbances according to the impaired function and resulted disability. Compensatory adjunctive pharmacotherapy or psychosocial interventions for overcoming this kind of communicative disturbances in the framework of modern integrated rehabilitation paradigm can be accounted as a triumph in this field. But this rehabilitative process needs to be  reinforced by more meticulous investigations in the future which can specify the interplay between basic pathology and resulted symptoms, whether deficit(negative) or excessive(positive) ones.  

Conclusion          
Conservative prescription of adjunctive drugs can be a useful strategy for making schizophrenic patients more prone to psychosocial interventions and in consequence increasing the effectiveness of rehabilitative programs. In this regard it seems that: 1) some of the Negative symptoms (like Affective Blunting and Anhedonia-Asociality) are more prone to be influenced by some specific adjunctive drugs (like SRIs and Maprotiline, respectively) and 2) some of the drugs (like, Maprotiline) are specifically more effective on some of the negative symptoms (like, Alogia and Anhedonia-Asociality) in comparison with the other ones (like, Avolition-Apathy).