PRACTICAL THERAPEUTICS eNS Drugs I (2): 107-118, 1994 1172-7047/94/0002-0107/S06.oo/0

© Adis International limited. All rights reserved

Options for the Treatment of Negative Symptoms of Schizophrenia Ian Coffey The Kennedy Tower, The Royal Edinburgh Hospital, Morningside Park, Edinburgh, Scotland

Contents Summary ............ . 1. The History of Positive versus Negative Symptoms 2. Type 1 and Type 2 Symptoms .. , , , , , , , 3, Differential Diagnosis of Negative Symptoms, , ,

3,1 Negative Symptoms and Depression '" 3,2 Negative Symptoms and Extrapyramidal Effects,

4, Negative Symptom Rating Scales , 5, Epidemiology of Negative Symptoms , 6, Treatment of Negative Symptoms

6,1 Traditional Antipsychotics , 6,2 Clozapine """ 6,3 Other Pharmacological Agents 6,4 Psychological Treatments ,

7, Conclusion and Treatment Recommendations

107 108 108 109 109 109 109 110 110 110 111 113 115 116

Summary The history of negative symptoms of schizophrenia, also known as fundamen­tal Bleulerian, Type 2 and deficit symptoms, is nearly as old as the concept of schizophrenia itself.

Negative symptoms include alogia, flattened affect, anhedonia, asociality, avolitionlapathy and attentional impairment. These symptoms can be assessed using various scales, such as the Andreasen's Scale for the Assessment of Nega­tive Symptoms (SANS), the Positive and Negative Symptom scale (PANSS), and the Negative Symptom Rating Scale (NSRS). The differential diagnosis of neg­ative symptoms requires exclusion of akinesia secondary to antipsychotic-in­duced extrapyramidal effects, and depression.

The issue of whether and to what extent negative symptoms of schizophrenia respond to traditional antipsychotic agents remains a controversial one. The atyp­ical antipsychotic, clozapine, appears to be an important agent in the treatment of negative symptoms, and initial data on several newly developed drugs suggest

108 Coffey

that they may prove to be useful. Psychological treatments are also a promising avenue for future research.

The symptoms of schizophrenia can be divided into positive and negative symptoms. These 2 types of symptoms respond differently to pharmacologi­cal treatment, with positive symptoms being more easily treated than negative ones. This review dis­cusses the definition and epidemiology of negative symptoms, and approaches to the treatment of these phenomena.

1. The History of Positive versus Negative Symptoms

Since the inception of the concept of schizo­phrenia, attempts have been made to classify and subdivide the condition and its symptoms. Kraepelin originated the concept of 'dementia praecox', which referred to a cluster of symptoms that are known today as schizophrenia. He believed that the disorder could be subdivided, and that dis­orders of different brain areas might manifest themselves in varying ways. For example, different types of dementia praecox could be due to effects in different areas of the brain, such as the frontal or temporallobes.[1]

Bleuler, who coined the term 'schizophrenia', paid particular attention to what he called the fun­damental symptoms. These included autism, am­bivalence, abnormalities of affect and attentional deficits, which are largely equivalent to the nega­tive symptoms known today. Bleuler considered symptoms such as delusions, hallucinations and catatonic symptoms, i.e. those considered to be positive symptoms, to be accessory symptoms)21 Therefore, the theory of positive versus negative symptoms is an old one, dating almost from the inception of the concept of schizophrenia itself. Ta­ble I summaries the positive and negative symp­toms of schizophrenia as defined today. Although different authors have used varying criteria for neg­ative symptoms all include poverty of speech and

© Adls Interna~onal Limited. All rights reserved.

flattening of affect. While these are known as symptoms, strictly speaking they are signs.

It has been conventionally held that Hughlings­Jackson[3] first distinguished between positive and negative symptoms of brain dysfunction. He sug­gested that negative symptoms were caused by a loss of function through damage to some specific brain area. In contrast, positive symptoms arose by release of function due to damage to some specific higher cortical area that inhibited that function. Positive symptoms were, therefore, regarded as secondary disinhibition phenomena.

Berrios,[41 however, traced the negative-posi­tive terminology to a discussion by Reynolds in 1858, and believes that it was DeClerambault who first emphasised the distinction between the 2 types of psychiatric symptoms.

2. Type 1 and Type 2 Symptoms

In 1980, Crow[S] proposed 2 types of schizo­phrenia. as opposed to types of symptoms. Type 1 syndrome consists of positive symptoms such as

Table I. Posnive and negative symptoms of schizophrenia

Negative symptoms Alogia (marked poverty of speech, poverty of content of speech)

Affective flattening (reduced emotional responsiveness)

Anhedonia (inability to feel pleasure)

Asociality (inability to feel intimacy, or to initiate or maintain social contacts)

Avolitionlapathy (inability to motivate oneself to do things, underachievement at work or school)

Attentional impairment

Positive symptoms Hallucinations

I ncoherence of speech

Delusions

Passivity phenomena Thought insertion, withdrawal and broadcast

Incongruity of affect (emotion)

eNS Drugs 1 (2) 1994

Treatment of Negative Symptoms of Schizophrenia

delusions and hallucinations. This was the syn­drome seen on initial presentation of the patient, was associated with normal brain structure, was responsive to antipsychotics and was not associ­ated with intellectual impairment.

Symptoms of Type 2 syndrome include affec­tive flattening, poverty of speech and loss of drive. These symptoms had a poor prognosis, with a lack of response to antipsychotics, enlarged cerebral ventricles and associated intellectual impairment. Type 2 symptoms were associated with underlying structural abnormalities.

Although, originally, Type 2 was considered to be a later stage of illness than Type 1, Crow revised this concept. In his later proposal, Type 1 and Type 2 processes could occur in the same patient, and were not mutually exclusive.[6]

3. Differential Diagnosis of Negative Symptoms

The presence or absence of positive symptoms and their severity are difficult to determine. How­ever, positive symptoms are not easily confused with other psychopathological features. This is not true of negative symptoms of schizophrenia which often have much in common with other conditions, such as depression and extra­pyramidal effects.

3.1 Negative Symptoms and Depression

An obvious potential difficulty is that of distin­guishing between negative symptoms such as flat­tening of affect, and depression. Anhedonia, apa­thy, social withdrawal and poverty of speech occur in both depressive illness and schizophrenia with predominantly negative symptoms.

KibeI and colleagues[7] in their study found some overlap between the specific phenomena of depressive illness and negative symptoms of schizophrenia. However, they concluded that sub­jective sadness, pessimism and suicidal intent be­longed to a depressive syndrome unrelated to negative symptoms of schizophrenia. Other phe­nomena such as observed sadness, lassitude and inability to feel emotions are negative symptoms

© Adis International Limited. All rights reserved.

109

of schizophrenia, and should be considered unreli­able measures of depression in the presence of schizophrenia.

3.2 Negative Symptoms and Extrapyramidal Effects

Another potential difficulty is that of distin­guishing antipsychotic-induced extrapyramidal adverse effects, such as bradykinesia, from nega­tive symptoms of schizophrenia. Although in its narrowest sense bradykinesia can be defined as a motor anomaly characterised by diminished arm swing, shortened stride and rigid posture, some in­vestigators take a broader view. They include such features as lack of emotional spontaneity, lack of or retarded speech, few gestures and generally decreased movement as characteristics of brady­kinesia.

Support for this view that bradykinesia may mimic some of the negative symptoms of schizo­phrenia, can be drawn from the findings of some antipsychotic dosage reduction studies. In these studies, patients receiving long term antipsychotic treatment showed improvement in items such as blunted affect, emotional withdrawal and psy­chomotor retardation after a reduction in drug dosage.[8]

4. Negative Symptom Rating Scales

Various rating scales have been developed to assess negative symptoms of schizophrenia. The Andreasen's Scale for the Assessment of Negative Symptoms (SANS) contains items for rating 30 negative symptoms.[9] The 5 main symptom com­plexes are alogia, affective flattening, avolition­apathy, anhedonia-asociality and attentional im­pairment.

Each of the 5 symptom complexes is defined and rated on a 6-point scale, the emphasis being on observable behaviour. The rating can also be based on the observations of nursing staff and, if avail­able, the observations of the patients' family.

For example, the avolition-apathy symptoms complex is composed of:

eNS Drugs 1 (2) 1994

110

• grooming and hygiene (zero indicates no evi­dence of poor grooming and hygiene, 5 indi­cates severe impairment with appearance extremely dishevelled);

• impersistence at work or school (i.e. the patient has had difficulty in seeking or maintaining em­ployment, or maintaining schoolwork, appro­priate for his or her age and gender);

• physical anergia (i.e. the tendency to remain in­ert and motionless);

• subjective complaints of avolition and apathy;

• global rating of avolition and apathy. Two other important negative symptom scales

are the Positive and Negative Symptom scale (PANSS)[lO] and the Negative Symptom Rating Scale (NSRS).[ll]

5. Epidemiology of Negative Symptoms

Data on the epidemiology of negative symp­toms of schizophrenia are difficult to interpret due to the lack of consensus about the nature of the symptoms.

Andreasen et a1J12] developed criteria for divid­ing schizophrenia into 3 subtypes; positive, nega­tive and mixed. They evaluated a consecutive sam­ple of 52 patients who had been admitted to a psychiatric hospital and fulfilled the Diagnostic and Statistical Manual of Mental Disorders III (DSM III) criteria for schizophrenia. 16 patients met criteria for negative schizophrenia, 18 for mixed and 18 for positive schizophrenia. The 3 groups differed in ways which were consistent with the nature of their different subtypes. Patients with negative schizophrenia had the least education, showed the worst premorbid adjustment and had a much reduced employment rate.

In the Chestnut Lodge study,[ l31 39 young pa­tients with schizophrenia, fulfilling Research Di­agnostic Criteria (RDC) criteria were assessed. 16 (41 %) had negative symptoms, such as psychomo­tor retardation (prevalence 5.6%), flattened affect (23.1 %) and poverty of speech (33.3%). At first follow-up, 2.5 years after hospital discharge, 21 (54%) were taking antipsychotic medication. 22

© Adls International Limited. All rights reserved.

Coffey

(56%) of the patients were taking antipsychotics at the end of the study,S years after discharge. Neg­ative symptoms remained over time, and were prognostic for poor functioning in the short and long (5 years) term.

Interestingly, negative symptoms appear to have a similar predominance across different cul­tures. Philips et al.[l41 noted 58% of 401 patients with schizophrenia from 4 different hospitals in China had prominent negative symptoms, when as­sessed at the time of admission. This compares well with the incidence of 41 % found in the Chestnut Lodge study performed in Illinois, USA.

6. Treatment of Negative Symptoms

6.1 Traditional Antipsychotics

The issue of whether negative symptoms re­spond to traditional antipsychotics is a controver­sial one. The issue is complicated by the finding that some negative symptoms may abate along with positive symptoms in response to antipsy­chotic treatment. [151

In a review, GoldbergLl6J cites some of the ear­lier studies of typical anti psychotics in schizophre­nia. Some trials demonstrated that negative symp­toms do respond to traditional antipsychotic agents. For example, a double-blind placebo-con­trolled trial of 340 newly admitted patients, found a highly significant difference between active an­tipsychotic treatment (chlorpromazine, fluphenaz­ine or thioridazine) and placebo for 6 weeks on a wide variety of symptoms.[l7] Symptoms such as indifference to the environment, apathy, inappro­priate affect, poor social participation and poor self care responded significantly to antipsychotic treat­ment. These symptoms are equivalent to symptoms that are traditionally regarded as negative symp­toms. Moreover, there was a greater development of symptomology (when the symptom had been absent at the time of entry into the trial) in placebo recipients than in patients receiving drug treat­ment. For example, in patients receiving placebo the pre- to post-treatment change in score for poor

eNS Drugs 1 (2) 1994

Treatment of Negative Symptoms of Schizophrenia

self care was 0.349, while in drug-treated patients the change was 1.283 (p < 0.01).

However, Goldberg[I6] points out that such a study would not be performed today, as it would be considered unethical to leave an acutely psychotic patient untreated by giving them placebo.

In contrast to these results, Johnstone and co­workers[I8] found that flupenthixol had no signif­icant effect on negative symptoms of schizophre­nia. In a double-blind trial, 45 patients acutely ill with schizophrenia were administered a-flu­penthixol or ~-flupenthixol (6 mg/day for 6 days followed by 9 mg/day for 22 days), or placebo. The a-isomer is the active variant of flupenthixol, while the ~-isomer is inactive and does not block dopamine receptors. a-Flupenthixol was signifi­cantly superior to the ~-isomer and to placebo in alleviating the positive symptoms of schizophre­nia, such as delusions, hallucinations and incon­gruity of affect. However, a-flupenthixol had no effect on negative symptoms, such as flattening of affect and poverty of speech.

Carpenter et al. [19] have conceptualised these residual negative symptoms as core or primary, and renamed them deficits. In their view, 'the contro­versy surrounding responsiveness of negative symptoms to antipsychotic drugs might be re­solved if primary, enduring deficit symptoms were distinguished from secondary, transitory negative symptoms'.

In general, as with positive symptoms, no par­ticular antipsychotic has been shown to be partic­ularly superior to any other in treating negative symptoms. There is some equivocal evidence that the diphenylbutylpiperidines (pimozide, fluspiril­ene and penfluridol) might have greater effects on negative symptoms than other agents. For exam­ple, Kolivakis et aU2D] conducted a double-blind study involving 51 patients who were randomly assigned to receive chlorpromazine (average daily dosage 216 mg/day) or pimozide (average daily dosage 7 mg/day) for 24 weeks. Patients in both treatment groups improved, but pimozide more ef­fectively alleviated emotional withdrawal.

© Adis International Limited. All rights reserved.

111

Similarly, Haas and Beckman,[2I] in a study of 30 patients compared pimozide 40 to 60 mg/day with haloperidol 40 to 60 mg/day for 4 weeks. They found that 10 patients receiving pimozide and 11 haloperidol recipients showed good or very good clinical response. Both groups of patients showed a significant decrease in Brief Psychiatric Rating Scale (BPRS). However, pimozide-treated patients but not haloperidol recipients had a significant im­provement in blunted affect and anergia. Neverthe­less, it must also be borne in mind that pimozide is less sedative than other antipsychotics, such as chlorpromazine and thioridazine. This effect is a confounding variable which may explain, at least in part, the apparent superiority of pimozide over haloperidol.

6.2 Clozapine

Clozapine is an atypical antipsychotic agent which is a member of the dibenzodiazepine group. However, unlike other members of this group such as loxapine and amoxapine, c10zapine does not cause significant extrapyramidal adverse effects. This is possibly due to its lower occupancy rate of dopamine D2 receptors compared with traditional antipsychotics.l22] Clozapine is also an antagonist of 5-HT2 (5-hydroxytryptamine; serotonin) recep­tors.[23]It has been speculated that this action may explain its efficacy in treating the negative symp­toms of schizophrenia. Prolactin levels are in­creased to a much lesser extent with c10zapine than traditional antipsychotics.[24]

6.2. 1 Efficacy in Treating Negafive Symptoms Initial investigations demonstrated that c1ozap­

ine had superior antipsychotic efficacy to tradi­tional antipsychotics. Furthermore, c10zapine in­duced fewer extrapyramidal effects and was less likely to cause tardive dyskinesia than traditional antipsychotics)25]

A subsequent trial involving 318 treatment-re­sistant patients with schizophrenia was initiated in the US. 392 inpatients from 16 participating cen­tres who fulfilled criteria for treatment-resistance were entered into a prospective 6-week phase. Pa­tients were administered haloperidol (up to 60

eNS Drugs 1 (2) 1994

112

mg/day or higher) and benzatropine (6 mg/day) to confirm their lack of responsiveness to typical an­tipsychotics. Improvement was defined as a 20% decrease in BPRS.f26] Five patients were judged to have responded to haloperidol, 52 terminated treat­ment early for a variety of reasons (these included poor tolerance of haloperidol, lack of cooperation, violation of the protocol and withdrawal of con­sent) and 248 were classified as nonresponders to haloperidol. The nonresponsive patients, plus 22 others who had been unable to tolerate haloperidol, were allowed to continue into the double-blind comparison phase. Clozapine 600 mg/day or chlor­promazine 1200 mg/day were administered for 6 weeks.

30% of patients treated with clozapine were categorised as responders compared with only 4% of chlorpromazine recipients. Clozapine produced a significantly greater improvement overall on the BPRS than chlorpromazine. Negative symptoms, such as emotional withdrawal, uncooperativeness and blunted affect, were also reduced to a more significant extent by clozapine than chlorprom­azine.

6.2.2 Dosage Tablets are available containing 25 and 100mg

of clozapine. The starting dosage is usually 25 to 50 mg/day, which can be increased gradually over 1 or 2 weeks up to 300 mg/day in divided doses. The dosage should be unevenly divided with the larger dose, of up to 200mg, being given at night. If required, dosage can be subsequently increased up to a maximum of 900 mg/day. The usual dosage is 200 to 450 mg/day.

6.2.3 Adverse Effects

Agranulocytosis Due to its profile as an effective antipsychotic

and its lack of extrapyramidal adverse effects, clozapine was introduced into Western European countries in the 1960s. However, in 1975 eight pa­tients receiving clozapine developed fatal agran­uiocytosisP71

Krupp and Barnes have shown that the risk of agranulocytosis in clozapine-treated patients is 1

© Adls International Limited, All rights reserved,

Coffey

to 2%, 10 times the risk of the disorder with con­ventional antipsychotics. However, regular white blood cell count monitoring can minimise the risk considerably.[28] White blood cell counts, includ­ing differentials, must be checked before onset of treatment and then weekly for the first 18 weeks of therapy, and fortnightly thereafter. If the total white cell count falls below 3000/mm3 or absolute neu­trophil count falls below 1500/mm3 treatment should be discontinued permanently.

Cardiovascular Effects Hypotension and tachycardia are the main ad­

verse cardiovascular effects observed during clozapine treatment.

Clozapine is an a-noradrenergic receptor antag­onist and it is this action which causes the hypoten­sive effect associated with the agent. Hypotension occurred in 26% of clozapine-treated patients in 1 study (Meltzer, unpublished data). Postural hypo­tension is relatively common in the first few weeks of treatment, but it generally settles without inter­vention. Hypotension can be minimised by grad­ually titrating dosage increments.

Tachycardia is due to the anticholinergic activ­ity of clozapine, and can persist for many months. ~-Adrenoceptor blockers have been used to counter this effect with some success (Meltzer, un­published data).

Electrocardiographic effects of clozapine in­clude widening of the QT interval, which can occur in up to 25% of recipients of the drug. Cardiac arrhythmias and conduction deficits, such as bun­dle branch block, are a contraindication to cloz­apine.

Tonic-Clonic Seizures Tonic-clonic (grand mal) seizures may occur

during clozapine treatment. This adverse effect is dosage dependent, being more likely to occur at dosages exceeding 600 mg/day. Povlsen et alJ29] noted an prevalence of seizures of 1.5% in patients treated with an average dosage of clozapine of 317 mg/day, and an prevalence of seizures of 4% was observed among patients treated with a mean dos­age of clozapine of 470 mg/dayPOl

eNS Drugs 1 (2) 1994

Treatment of Negative Symptoms of Schizophrenia

In patients who develop seizures, halving of the preseizure dosage of clozapine and the addition of normal anticonvulsant dosages of valproic acid (sodium valproate) has been recommended. [3 1]

Carbamazepine should be avoided as it, like clozapine, can have a bone marrow suppressing ef­fect. Valproic acid, and phenytoin, may interact with clozapine, causing a decrease in plasma clozapine concentrations. Therefore, an increase in clozapine dosage may be required after anticonvul­sant therapy has been initiated. [3 1]

Other Adverse Effects Initial hypersalivation can be troublesome for

about a third of patients receiving clozapine, but this generally settles down. If it continues to be problematic, anticholinergic agents or a reduction in the dosage of clozapine can be tried. Clozapine­induced sedation and bodyweight gain can also oc­cur at the beginning of therapy.

6.2.4 Contraindications Clozapine should be avoided in patients with a

history of blood dyscrasias or bone marrow sup­pression. Because of the risk of agranulocytosis, clozapine is currently recommended only for those patients who are resistant to, or intolerant of, con­ventional antipsychotic medication. If compliance with blood monitoring cannot be guaranteed, use of clozapine is contraindicated.

It is unclear as to whether AIDS is an absolute contraindication, although clozapine should obvi­ously be avoided in the advanced stages of HIV infection. It should be administered with caution in patients with cardiovascular disorders and prosta­tism because of its anticholinergic effects.

Generally, clozapine should be administered alone rather than in combination with a typical an­tipsychotic. There have been no controlled trials demonstrating the usefulness of augmenting typi­cal antipsychotics with clozapine, and there is the, at least theoretical, risk that this combination may be more likely to cause bone marrow sup­pression.

An additional reason for avoiding the combina­tion of clozapine and traditional antipsychotics is based on more theoretical grounds. The efficacy of

© Adis International Limited. All rights reserved.

113

clozapine is thought to be mediated through a com­bination of weak D2 and potent 5-HT2 receptor ac­tivity. Potent D2 blockade by a conventional anti­psychotic, therefore, may inhibit the antipsychotic effect of clozapine.

6.3 Other Pharmacological Agents

It is beyond the scope of this article to describe all the new agents that are being assessed for the treatment of schizophrenia and, in particular, the negative symptoms of the disorder. For a more comprehensive overview, readers are directed to the review by Gerlach. [32]

6.3. I Risperidone Risperidone, a 5-HT2 and D2 receptor antago­

nist, is a benzisoxazole derivative. It has been in­vestigated as a treatment for the negative symp­toms of schizophrenia in a study of 44 patients with chronic schizophrenia)33] Patients underwent a 2-week run-in period with their existing antipsy­chotic medication, followed by a I-week washout period. Risperidone or haloperidol were then ad­ministered for 12 weeks. Five patients from the haloperidol group and 1 from the risperidone group dropped out.

At the end of treatment the mean dosage of risperidone was 12 mg/day and of haloperidol was 10 mg/day. Negative symptoms improved in both groups as assessed with the PANSS. Although the improvement was more pronounced in risperidone recipients after 8 weeks of treatment, there was no significant difference between the effects of the 2 drugs.

6.3.2 Benzodiazepines Alprazolam has been reported to be of benefit

as a supplement to antipsychotics in the treatment of the negative symptoms of schizophrenia.

An initial open trial with 8 patients showed an apparent beneficial effect of combined antipsy­chotic and alprazolam therapy)34] However, a fol­low-on placebo-controlled trial of alprazolam sup­plementation failed to show a significant effect on negative symptoms.[35] In this trial, 55 patients with schizophrenia with demonstrable negative

eNS Drugs 1 (2) 1994

114

symptoms on the BPRS were treated for a mean of 5 to 6 weeks. 18 patients received alprazolam (mean dosage 4.2 mg/day), 20 patients received diazepam (mean dosage 40.4 mg/day) and 17 re­ceived placebo in addition to antipsychotic ther­apy. Although a mild and temporary initial benefi­cial effect was noted in patients receiving alprazolam supplementation, the combination did not appear to have a sustained beneficial effect on negative symptoms.

Furthermore, it is clear that therapy with benzodiazepines has its own problems, notably drug withdrawal syndrome and the potential prob­lem of dependence.

6.3.3 Antidepressants Bucci[36] has reported that tranylcypromine im­

proved negative symptoms significantly in 154 chronically schizophrenic patients with marked negative symptoms. Interestingly, tranylcypro­mine has some amphetamine-like activity, aug­menting dopamine activity in the brain. All of the patients in this study were being concomitantly treated with antipsychotics.

More recently, fluoxetine has been reported to be of potential benefit in the treatment of negative symptoms.[37] 14 outpatients with DSM-I1I-R cri­teria for schizophrenia and schizoaffective disor­der were entered into a trial of fluoxetine supple­mentation of antipsychotic treatment. Nine patients completed the 6 week trial. They were re­ceiving a variety of antipsychotics, with a mean

chlorpromazine equivalent dosage of 900 ± 44.7 mg/day. At week 6 the mean scores for negative ratings on the BPRS and Scale for Assessment of Negative Symptoms were significantly re­duced.

However, as this was an open trial, the authors conceded that these findings can only be consid­ered preliminary, pending replication of this result in well designed and controlled trials.

6.3.4 Ritanserin Ritanserin, the selective 5-HT2 and 5-HTIC an­

tagonist, has been found to reduce negative symp-

© Adis International Limited, All rights reserved,

Coffey

toms in a recent double-blind placebo-controlled trial. [38]

33 patients with schizophrenia and prominent negative symptoms were entered into the trial. 19 patients had ritanserin added to their usual antipsy­chotic treatment, while 14 other patients received supplementation with placebo for 6 weeks. The dosage of ritanserin was initially 10 mg/day, al­though an increase in dosage to 20 mg/day after 2 weeks and 30 mg/day after 4 weeks was allowed. Ritanserin reduced significantly the negative symptoms on the SANS. The main effects were observed on the items of facial expression, global affective flattening, and relationships with friends and peers.

6.3.5 Other Miscellaneous Agents Many other pharmacological agents have been

investigated as treatments for treatment-resistant schizophrenia and for the negative symptoms of schizophrenia.

Agents such as opioids (e.g. methadone[39]), op­ioid antagonists (e.g. naloxone[40]) and calcium channel blockers (e.g. verapamil[41,42]) have been studied, but none have been shown to consistently improve negative symptoms in appropriately de­signed trials.

The antipsychotic activity of ondansetron, a 5-HT3 antagonist, has been investigated in hos­pitalised patients with acute schizophrenia. An an­tipsychotic effect was observed at low dosages (4 to 8 mg/day), while high dosages were less effec­tive.f32] These preliminary findings are encourag­ing, and results from double-blind trials are awaited with interest.

Levodopa has been used to treat negative symp­toms. However, some patients, especially those with marked positive symptoms,[43] may experi­ence worsening of positive symptoms.[44] There­fore, patients with mainly negative symptoms would be expected to benefit most from this agent. There do not appear to be any major problems as­sociated with concomitant use of levodopa and an­tipsychotics.f45]

Like levodopa, amphetamines augment brain dopamine activity, and may be of some benefit in

eNS Drugs 1 (2) 1994

Treatment of Negative Symptoms of Schizophrenia

Table II. Agents used to treat negative symptoms of schizophrenia

Agent Route of administration

Typical anti psychotics Phenothiazines

Chlorpromazine

Thioridazine

Trifluoperazine

Fluphenazine

Thioxanthenes

Flupenthixol

Zuclopenthixol

Butyrophenones

Haloperidol

Droperidol

Dipheny/buty/piperidones

Pimozide

Fluspirilene

Substituted benzamides

Sulpiride Remoxipride

Atypical antipsychotics Risperidone Clozapine

Other agents Fluoxetine Ritanserin

Oral

Oral Oral

Deep intramuscular injection

Deep intramuscular injection

Deep intramuscular injection

Oral

Oral

Intramuscular

Oral

Deep intramuscular injection

Oral Oral

Oral

Oral

Oral Oral

patients with schizophrenia.[46] However, obvi­ous ethical difficulties, such as the risk of de­pendence, preclude the routine clinical use of amphetamines.

6.4 Psychological Treatments

6.4. 1 Behavioural Modification Psychological treatments for the negative

symptoms of schizophrenia have been reviewed by Slade and Bentall.l47] Behavioural modification

© Adls International Limited. All rights reserved.

Dosage

600-1500 mglday 600-1500 mg/day

5-50 mglday

115

Test dose of 12.5mg (6.25mg in elderly patients), after 4-7 days administer 12.5-1 OOmg, repeat at intervals of 14-40 days, adjusted according to response

Test dose of 20mg, after 5-10 days administer 20-40mg, repeat at intervals of 2-4 weeks, adjusted according to response. Maximum 400mg weekly

Test dose of 100mg, after 7-28 days administer 200-400mg, repeat at intervals of 2-4 weeks, adjusted according to response. Maximum 600mg weekly

1.5-20 mglday in divided doses, gradually increasing up to 100 mglday 5-20mg every 4-8 hours

Up to 10mg, repeated every 4-6 hours if necessary

20 mglday initially in divided doses, adjusted according to response. Maximum daily dosage 60mg

2mg, increasing by 2mg at weekly intervals according to response. Maximum 20mg weekly

600-1800 mglday 150-600 mglday

10-30 mglday

200-450 mglday. Maximum 900 mglday

20 mglday 10-30 mglday

techniques were investigated extensively in the US during the 1950s and 1960s, particularly those techniques based on the principles of operant con­ditioning. The basis of operant conditioning is that an organism tends to repeat actions that result in a pleasurable or beneficial effect. Such effects are known as positive reinforcements. The behaviour­al techniques that arose from operant conditioning came to be known as the token economy ap­proach.l48]

eNS Drugs 1 (2) 1994

116

The token economy regimen used 'tokens' to help motivated patients to behave more appropri­ately. The tokens could be exchanged for positive reinforcements such as cigarettes, the opportunity to watch television, or the chance to sleep in a sin­gle room rather than a dormitory.

Although token economy regimens do appear to be of some benefit to patients with negative symp­toms, they require highly motivated, well trained staff who largely share common objectives. In ad­dition, favourable staff to patient ratios are re­quired. Furthermore, the benefits of the token economy often fail to generalise,[49] i.e. once the regimen is withdrawn the patient tends to revert to previous maladaptive behaviours. A further criti­cism of this type of treatment is that some research suggests that the effectiveness of token regimens is more dependent on the change in the quality of the relationship between the patients and his/her carers than the actual contingency between tokens and behaviour)50]

6.4.2 Social Skill Training Social skill training appears to have only a tran­

sient effect on the negative symptoms of schizo­phrenia, without any evidence of long term bene­ficial effects)51]

6.4.3 Problem Solving Approaches Influenced by the growing trend towards more

cognitively based approaches, Hansen et al)52] trained 7 patients, 6 of whom had schizophrenia, to carry out procedures aimed at solving interper­sonal problems. It was claimed that this approach produced positive results which could be carried over into nontraining settings. They also claimed that these benefits persisted for up to 4 months after treatment stopped. A preliminary report using a cognitive shift neurocognitive training module[53] has shown promising results, although only 3 pa­tients were involved.

7. Conclusion and Treatment Recommendations

The concept of a differentiation of symptoms of schizophrenia into positive and negative symp-

© Adls International limited. All rights reserved.

Coffey

toms is as old as the concept of schizophrenia itself. Negative symptoms include alogia, affective flat­tening, anhedonia, asociality, apathy and atten­tional impairments. Positive symptoms, such as de­lusions and hallucinations, may coexist with negative symptoms.

Antipsychotics have less effect on negative than positive symptoms. In patients in whom negative symptoms do not respond to a standard dosage of an antipsychotic, a number of alternative ap­proaches can be taken:

• Ensure compliance with the standard dosage of an antipsychotic (see table II).

• Increase antipsychotic dosage (see table II).

• If a sedative drug effect or pseudo-Parkinsonian effect (due to akinesia) is suspected, decrease antipsychotic dosage or change to a less sedat­ing antipsychotic, such as haloperidol or triflu­operazine (table II).

• Reassess the diagnosis to ensure that differen­tial diagnoses, such as depression, can be ex­cluded.

• If the patient continues to have persistent dis­abling negative symptoms, consider clozapine (after ensuring that the patient is suitable for this treatment and there are no contraindications [see section 6.2.5 and table II]).

• Consider supplementation of traditional anti­psychotics with agents such as fluoxetine or ritanserin (see table II). However, it must be borne in mind that none of these agents has out­performed conventional antipsychotics.

• Consider concomitant use of psychological treatments, such as social reinforcement, so­cial skill training and token economies, as well as more recently developed cognitive techniques.

References I. Kraepelin E. Dementia praecox and paraphrenia. Edinburgh: E

& S Livingstone, 1919 2. Bleuler E. Dementia praecox or the group of schiwphrenias?

Translated by Zinkin J. New York: International Universities Press, 1950

eNS Drugs 1 (2) 1994

Treatment of Negative Symptoms of Schizophrenia

3. Jackson JH. On postepileptic states: a contribution to the com­parative study of insanities. J Ment Sci 1889; 35: 490-500

4. Berrios GE. Positive and negative symptoms and Jackson: a conceptual history. Arch Gen Psychiatry 1984; 42: 95-7

5. Crow TJ. Molecular pathology of schizophrenia; more than one disease process. BMJ 1980; 280: 1-9

6. Crow TJ. The two syndrome concept; origins and current status. Schizophr Bull 1985; 11: 471-86

7. Kibei DA, Laffont I, Liddle PF. The composition of the negative syndrome of chronic schizophrenia. Br J Psychiatry 1993; 162: 744-50

8. Marder SR, Van Putton T, Mintz J, et al. Costs and benefits of two doses of fluphenazine. Arch Gen Psychiatry 1984: 41; 1025-9

9. Andreasen NC. Negative symptoms in schizophrenia; defini­tion and reliability. Arch Gen Psychiatry 1982; 39: 784-8

10. Kay SR, Fishbein A, Opler LA. The positive and negative syn­drome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-76

11. Lager AC, Kirch DG, Wyatt RJ. A negative symptom rating scale. Psychiatry Res 1985; 16: 27-36

12. Andreasen NC, Olsen S. Negative v positive schizophrenia. Arch Gen Psychiatry 1982; 39: 789-94

13. Pogue-Gei1e MF, Harrow M. Negative symptoms in schizo­phrenia: their longitudinal course and prognostic importance. Schizophr Bull 1985; 11: 12

14. Philips M, Zhao Z, Zhang Xiong X. Changes in positive and negative symptoms of schizophrenic inpatients in China. Br J Psychiatry 1991; 159: 226-31

15. Davis J. Antipsychotic drugs. In: Kaplan HI, et aI., editors. Comprehensive psychiatry. 3rd ed. Baltimore: Williams & Wilkins, 1980: 2257-89

16. Golberg Sc. Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophr Bull 1985; 11: 453-6

17. Goldberg SC, Klerman GL, Cole JO. Changes in schizophrenic psychopathology and ward behaviour as a function of pheno­thiazine treatment. Br J Psychiatry 1965; Ill: 120-33

18. Johnstone EC, Crow TJ, Frith CD, et al. Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet 1978; i: 848-51

19. Carpenter Jr WT, Heinrichs DW, Alphs LD. Treatment of neg­ative symptoms. Schizophr Bull 1985 II: 440-52

20. KoJivakis T, Azian H, Kingstone E. A double blind comparison of pimozide and chlorpromazine in the maintenance of chronic schizophrenic patients. Current Therapeutic Research 1974; 16: 998-1004

21. Haas S, Beckman H. Pimozide versus haloperidol in acute schizophrenia: a double blind controlled study. Phar­macopsychiatry 1982; 15: 70-4

22. Farde L, Nordestrom AL. PET analysis indicates atypical cen­traJ dopamine occupancy in c10zapine treated patients. Br J Psychiatry 1992; 160 Suppl. 17: 30-3

23. Peroutka SJ, Synder SH. Relationship of neuroleptic drug ef­fects at brain dopamine, serotonin, adrenergic and histamine receptors to clinicaJ potency. Am J Psychiatry 1980; 137: 1518-23

24. Meltzer HY, Daniels S, Fang VS. Clozapine increases rat serum prolactin levels. Life Sci 1975; 17: 339-42

25. Casey DE. Clozapine, neuroleptic induced EPS and tardive dys­kinesia. Psychopharmacology 1989; 99: 547-53

© Adis International Limited. All rights reserved.

117

26. Kane JM, Honigfeld G, Singer J, et al. Clozapine for the treat­ment resistant schizophrenia: a double blind comparison ver­

sus chlorpromazine/benztropine. Arch Gen Psychiatry 1988; 45: 789-96

27. Amsler HA, Teerenhovi LB, Artha E. Agranulocytosis in pa­tients treated with clozapine: a study of the Finnish epidemic. Acta Psychiatr Scand 1977; 56: 241-8

28. Krupp P, Barnes P. Leponex-associated granulocytopenia: a re­view of the situation. Psychopharmacology 1989; 99 Supp!.: S118-21

29. Povlsen VJ, Noring V, Fog T, et al. Tolerability and therapeutic effect of clozapine. A retrospective investigation of 216 pa­tients treated with clozapine for up to 12 years. Acta Psychiatr Scand 1985; 71: 176-85

30. Lindstrom LH. The effect of long term treatment with c10zapine

in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988; 77: 524-9

31. Meltzer HY. Treatment of the neuroleptic nonresponsive schiz­ophrenic patient. Schizophr Bull 1992; 18: 515-34

32. Gerlach J. New Antipsychotics: classification, efficacy and ad­verse effects. Schizophr Bull 1991; 17: 289-310

33. Claus A, Bollen J, De Cuyper H, et a!. Risperidone versus hal­operidol in the treatment of chronic schizophrenic inpatients; a multicentre double blind comparative study. Acta Psychiatr Scand 1992; 85: 295-305

34. Czernansky JG, Lombroso L, Guslevich G. Treatment of schiz­ophrenics with alprazolam: a preliminary open label study. J

Clin Psychopharmacol 1984; 4: 349-52 35. Czernansky JG, Riney SJ, Lombrozo L, et al. Double-blind

comparison of alprazolam, diazepam and placebo for the

treatment of negative symptoms. Arch Gen Psychiatry 1988; 45: 655-9

36. Bucci L. The negative symptoms of schizophrenia and M.A.O.J's. Psychopharmacology 1987; 91: 104-8

37. Goff DC, Brotman AW, Waites M. A trial of fluoxetine added to neuroleptics for treatment resistant schizophrenic patients. Am J Psychiatry 1990; 147: 492-4

38. Duinkerke SJ, Botter PA, Jansen AA. Ritanserin, a selective 5-HT211c antagonist, and negative symptoms in schizophre­nia; a placebo-controlled double-blind triaJ. Br J Psychiatry 1993; 164: 451-5

39. Brizer DA, Hartman N, Sweeney J. Effect of methadone plus neuroleptics on treatment-resistant chronic paranoid schizo­phrenia. Am J Psychiatry 1985; 142: 1106-7

40. Pickar D, Bunney WE, Douillet P. Repeated naloxone adminis­

tration in schizophrenia. A phase II World HeaJth Organisa­tion study. BioI Psychiatry 1989; 25: 440-9

41. Grebb JA, Shelton RC, Taylor EH. A negative douhle blind, placebo-controlled trial of verapamil in chronic schizophre­nia. BioI Psychiatry 1986; 21: 691-4

42. Schepelern S, Koster A. Verapamil in the treatment of severe schizophrenia. Acta Psychiatr Scand 1987; 75: 557-8

43. Inanaga K, Inovee K, Tachibana H, et al. Effect of L-Dopa in schizophrenia. Folia Psychiatr Neurol Japan 1972; 26: 145-7

44. Angrist B, Sathananthan G, Gerson S. Behavioural effects of L-Dopa in schizophrenic patients. Psychopharmacology 1973; 31: 1-12

eNS Drugs 1 (2) 1994

118

45. Christison GW, Kirch DG, Wyatt RJ. When symptoms persist; choosing among alternative somatic treatments in schizo­phrenia. Schizophr Bull 1991; 17: 217-46

46. Angrist B, Rotrosen J, Gershon S. Differential effects of am­phetamines and neuroleptics on negative versus positive symptoms in schizophrenia. Psychopharmacology 1980; 72: 17-9

47. Slade P, Bentall R. Psychological treatment for negative symp­toms. Bf J Psychiatry 1989; 155 Suppl. 7: 133-5

48. Ayllon T, Azrin NH. The token economy. New York; Appleton­Century-Crofts, 1968

49. Bebbington PE, Kuipers L. Non-physical treatment of the psy­choses. BMJ 1987; 43: 704-7

50. Baker R, Hall IN, Hutchinson K, et al. Symptom changes in chronic schizophrenic patients on a token economy: a control­led experiment. Br J Psychiatry 1977; 131: 381-93

© Adis International limited. All rights reserved

Coffey

51. Curran JP, Monti PM, editors. Social skills training. A practical handbook for assessment and treatment. New York: Guilford Press, 1982

52. Hansen DJ, Lawrence JSS, Christoff KA. Effects of interper­sonal problem-solving with chronic aftercare patients on problem-solving component skills and effectiveness of solu­

tions. J Consult Clin Psychol1985; 53: 167-74 53. Delahunty A, Morice R, Frost B. Specific cognitive flexibility

rehabilitation in schizophrenia. Psychol Med 1993; 23: 221-7

Correspondence and reprints: Dr Ian Coffey, The Kennedy Tower, The Royal Edinburgh Hospital, Morningside Park, Edinburgh, EHlO 5HF, Scotland.

eNS Drugs 1 (2) 1994