Neuroleptics Side Effect Correctors

Among them emit drugs with stimulating properties and drugs with sedative properties. Stimulating drugs include trihexyphenidyl (cyclodol), orphenadrin , biperiden (akineton), triperiden (norakine), to sedatives - benaktizin ( amisyl ), dietasin (deparkin), tropatepine (lepticur), diphenyltropine (tropacin), profenamin (etopropazin), procyclidine , benztropine (cogentin). Stimulatory correctors are preferably used when patients have deficient (negative) symptoms in order to enhance the stimulating effects of neuroleptics, sedatives - especially in agitated psychosis ^[2] . In practice, cyclodol and akineton are most often used as anti-psychotic correctors in Russia from anticholinergic drugs ^[3] .

Cyclodol

Anticholinergic drugs are most effective for neuroleptic parkinsonism and acute dystonia , to a lesser extent - for akathisia and tremor . In late dyskinesia, these drugs are not used, as they can enhance its severity ^[1] . Although anticholinergics have proven to be effective in neuroleptic parkinsonism and acute dystonia, their clinical usefulness with the prevalence of akathisia in patients remains unproven ^[4] ; preference in treating patients with akatisia can be given only in cases where patients simultaneously have symptoms of akathisia and parkinsonism ^[5] .

The effect of anticholinergic drugs on extrapyramidal disorders is due to their ability to block central acetylcholine muscarinic receptors ^[6] (moreover, among the anticholinergic correctors, one can select selective, which are antagonists of only M ₁ receptors, and non-selective, with the ability to block M ₁ , M ₂ , M ^[7] ). Since dopamine inhibits the release of acetylcholine in the striatum , the use of antipsychotics, which have the ability to block dopamine, entails an increase in the release of acetylcholine in the striatum. This leads to an imbalance of acetylcholine and dopamine, which, as is sometimes claimed, is a key element in the occurrence of extrapyramidal disorders. Anticholinergic drugs restore the disturbed balance of the dopaminergic and cholinergic systems. Their additional effects include antihistaminergic action and possible blockade of dopamine reuptake ^[6] .

Anticholinergic correctors are usually used to relieve extrapyramidal disorders that have already developed, less often for their prevention, since they can reduce the effectiveness of neuroleptic therapy and lead to the development of anticholinergic side effects . Contraindications to the reception of anticholinergic correctors are, in particular, angle - closure glaucoma , prostate adenoma , intestinal obstruction ^[1] . These drugs can in standard clinical doses can impair the cognitive functions of patients ^[8] ; in addition, their reception sometimes leads to their abuse due toanxiolytic properties and the ability to cause euphoria ^[9] , the emergence of drug dependence ^{[8] [10]} . There is the concept of tsiklodolovoy toxicomania ^[11] . The use of anticholinergic correctors is also associated with the risk of tardive dyskinesia, memory disorders, excessive sedation , hyperthermic conditions, changes in plasma concentration of neuroleptics ^[12] , hyperglycemia and other metabolic complications ^[8] .

The opinion is often expressed that the appointment of anticholinergic correctors simultaneously with the appointment of antipsychotics for the prevention of extrapyramidal disorders is unacceptable, they should be prescribed only for the treatment of neuroleptic extrapyramidal disorders that have already arisen ^{[8] [10] [13]} . For example, the Oxford Psychiatric Handbook stresses that anticholinergic correctors cannot be used routinely, as they increase the risk of tardive dyskinesia ^[14] . Other authors advocate the prophylactic use of anticholinergic correctors, emphasizing that their early administration reduces the frequency of extrapyramidal disorders; at the same time, mutual understanding between the patient and the doctor is improved, and the patient's agreement on the continuation of neuroleptic therapy is facilitated ^[12] .

A review of 6 studies in which anticholinergic correctors were prescribed prophylactically performed in different countries yielded contradictory results: the authors of three of these studies concluded that there was no need for a preventive assignment of correctors, other researchers, on the contrary, decided that such an appointment was necessary and reasonable ^[12] .

It is also suggested that in order to minimize the risk of side effects, instead of trihexyphenidyl (cyclodol), biperidine (akineton) should be used, which, due to the selective effect on a certain subtype of muscarinic receptors (M ₁ ), less often causes peripheral anticholinergic side effects; in addition, it affects memory and attention less and does not potentiate the sedative effect of neuroleptics. Biperiden has a lower than trihexyphenidyl risk of confusion and anticholinergic delirium and a lower risk of abuse ^[12] . It is believed that selective anticholinergics have some advantages due to their mechanism of action: in particular, they selectively affect the receptors located on the neurons responsible for the formation of extrapyramidal disorders; The same applies to biperidine, which, being a selective anticholinergic, has advantages over the non-selective antagonist of M-cholinergic receptors trihexyphenidyl in terms of therapeutic effect on extrapyramidal disorders ^[7] .

Authors who speak out against the routine use of anticholinergic correctors emphasize that as tolerance to neuroleptics develops, the need for the use of anticholinergic drugs disappears, therefore their doses need to be revised periodically, gradually reducing them. The sudden cancellation of anticholinergic drugs can cause weights in parkinsonism, since the nervous system forms some physical dependence on them ^[10] .

In extrapyramidal disorders

As a rule, levodopa drugs and dopamine receptor agonists in patients with psychotic disorders who have developed neuroleptic extrapyramidal disorders are not prescribed, since these drugs can cause worsening of the primary psychotic illness about which antipsychotics are prescribed. However, they can be assigned for a short time if the patient does not suffer from a mental disorder and has taken a neuroleptic as an antiemetic or metoclopramide (which has an effect similar to neuroleptics and can also cause extrapyramidal disorders), and its abolition did not lead to a rapid regression of extrapyramidal symptoms ^[3] .

Amantadine can also be used in patients with mental disorders in neuroleptic parkinsonism, although its effectiveness has not been established as clearly as with anticholinergic correctors. Nevertheless, the use of amantadine is advisable in elderly patients who can tolerate it better than anticholinergic correctors, as well as in patients with tardive dyskinesia. The mechanism of action of amantadine is associated with blockade of NMDA-glutamate receptors , increased release of dopamine from presynaptic endings, a slight anticholinergic action. In severe cases of extrapyramidal disorders, a combination of biperidine and amantadine can be prescribed ^[3] .

Dopaminergic drugs have also proven their effectiveness in akathisia ^[15] .

With hyperprolactinemia

Most of the existing neuroleptics cause hyperprolactinemia (increased levels of the hormone prolactin in the blood), which can lead to a number of serious somatic side effects. Preference in the treatment of hyperprolactinemia is given to central and peripheral dopamine receptor stimulants, such as bromocriptine , lizrid , pergolid , Amantadine , Lergotril, Parlodel LAR, Cabergoline (Dostinex). The most common of these drugs received bromocriptine. Some patients with hyperprolactinemia are resistant to treatment with these drugs, and to reduce the level of prolactin, increased doses of them are required, which leads to an increased risk of possible complications. In this regard, a new D ₂ - quinagolide agonist was developed (norprolac) ^[16] , which, unlike a number of other dopaminomimetics used in the treatment of hyperprolactinemia, does not belong to the derivatives of ergot alkaloids ^[17] and normalizes the content of prolactin in patients resistant to bromocriptine ^[16] .

The disadvantage of bromocriptine therapy is the severity of side effects, such as, in particular, dyspepsia , orthostatic hypotension ^[18] , syncopal conditions , nausea and vomiting, constipation, symptoms of reflux esophagitis , headaches, insomnia ^[19] . Cabergoline and quinagolide differ from bromocriptine in better tolerability ^[18] . They are more selective than bromocriptine, interact with D ₂ receptors ^[19] . The side effects of cabergoline and quinagolide are partially similar to the side effects of bromocriptine, but are usually milder ^[19] ; however, cabergoline is effective in most patients resistant to treatment with bromocriptine and quinagolide ^[20] .

Although researchers note that the use of dopamine agonists for the correction of hyperprolactinemia in psychiatric practice can lead to a decrease in the effectiveness of neuroleptic therapy and exacerbate psychopathological symptoms, it is also emphasized that gradual titration and the use of moderate doses of dopamine agonists avoid the exacerbation and decrease the effectiveness of neuroleptic therapy ^[21] . It should also be noted that mental disorders of anxiety , depression and psycho-vegetative nature, are secondary to hyperprolactinemia successfully amenable to correction with dopamine agonists - bromocriptine, cabergoline and quinagolide, with positive changes are observed even in cases of laboratory ineffectiveness of dopamine agonists, ie patients with persisting excessive content of prolactin ^[19] .

Contraindications to the use of corrective therapy with dopamine agonists are severe forms of cardiovascular diseases , hypersensitivity to proofreaders, pregnancy , breastfeeding, and the psychotic state of the patient ^[21] .

With acute dystonia

In addition to anticholinergic correctors, in acute dystonia it is also possible to use benzodiazepines ^[22] (in particular, lorazepam ^[22] , diazepam ^[9] , phenazepam , nozepam , elenium ^[23] ) or the combined use of aminazine intramuscularly and 20% caffeine subcutaneously ^{[24 ]} (instead, it is also possible to use strong tea or coffee ^[23] ); in generalized acute dystonia, the simultaneous administration of aminazine or teasercine intramuscularly and anticholinergic correctors (akineton) intramuscularly ^[24] .

In some Russian and Western sources, it is recommended to administer intravenous antihistamines ( diphenhydramine ), caffeine sodium benzoate ^{[25] [26] [27]} , benzodiazepines (diazepam, lorazepam) ^[28] or barbiturates ^[25] in severe cases.

When akatiziya

Beta-blockers, clonidine , benzodiazepines are used especially widely in the treatment of akathisia ^[29] . Lipophilic beta-blockers, such as propranolol , are among the most effective agents in the treatment of akathisia ^[5] . Benzodiazepines also have some efficacy, presumably due to their non-specific anti-anxiety and sedative properties ^{[4] [5]} . There is also an opinion that drugs that reduce the activity of norepinephrine neurons should be prescribed as correctors in akathisia, namely, beta-adrenoblockers and benzodiazepines are such drugs ^[7] . Antihistamines ^[6] , valproat ^{[30] [31]} , pregabalin , gabapentin , carbamazepine , baclofen , α ₁ -adrenoblockers ^[15] , 5-HT ₂ -receptor blockers (in particular, cyproheptadin , ritanserin , antidepressants mianserin ^[28] and - in low doses - mirtazapine ) ^[4] .

The above-mentioned drugs relate mainly to the first-line drugs in the treatment of akathisia. There are very few RCT data for treating akathisia “beyond the limits of the first line” ^[15] , however, if the above mentioned drugs prove to be ineffective or insufficiently effective in a particular case, amantadine , buspirone can be used , amitriptyline ^[29] , vitamin B6 ^[32] , antioxidants (vitamins E and C ), omega-3 fatty acids , tizanidine , memantine , testosterone , pregnenolone , dehydroepiandrosterone , estrogen replacement therapy in post-menopausal women ^[15] ; codeine and other opioids ^[28] .

Drugs of choice for late akathisia are sympatholytics ( reserpine , tetrabenazine ), opioids are also effective. When iron deficiency is necessary to compensate for it ^[28] .

Late dyskinesia

Currently, there are no uniformly defined formalized algorithms for the treatment of tardive dyskinesia ^[6] . The efficacy of many drugs used to treat this disorder has not been proven or insufficiently proven ^{[33] [34] [35] [36] [37] [38] [39] [40]} . Nevertheless, there are data in favor of levodopa, hydroxypertina sodium valproate , tiaprid , vitamin E ^[41] , melatonin , high doses of vitamins , various antioxidants ^[42] , tetrabenazine ^[43] . Valbenazine is approved for the treatment of tardive dyskinesia in the United States ^[44] . In patients with late dystonia , the use of anticholinergics and botulinum toxin is desirable ^[45] .

Russian authors advise using certain drugs ( GABA agonists, reserpine , sulpiride or olanzapine , carbamazepine , calcium antagonists , cholinergic transmission enhancers, anticholinergics, beta-blockers, etc.) depending on the type of hyperkinesis prevailing in the clinical picture of late dyskinesia ^{[24] [46]} . It is also recommended to use nootropic ^{[24] [26]} , lithium , lecithin , physostigmine ^[26] , amantadine sulfate, clonazepam ^[9] , antioxidant preparations ( vitamin E and other antioxidants ) ^{[26] [47]} .

• Parkinsonian