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Mania is for practical purposes the mirror image of depression. Approximately 50% of people affected present with an elated, euphoric mood. They may be grandiose in their attitudes and beliefs uninhibited in their behaviour. However, the remainder may be irritable and tetchy rather than elated and euphoric and paranoid rather than grandiose. Common to both groups is an increased level of activity, so that hyperactivity is perhaps the most consistent diagnostic feature of mania. In addition, there is typically an increase in appetite and a decrease in time spent asleep.

In 1853, Falret and Baillarger independently described a bipolar disorder, in which affected individuals cycled between periods of elation, or mania, and depression. This was variously called folie circulaire or folie à deux periodes. It forms the basis for what is now recognised as manic-depressive disorder. In 1896, Emil Kraepelin divided the major psychiatric illnesses into manic-depressive illness and schizophrenia. The former was primarily a disorder of mood, the latter a disturbance of cognitive functions. The former usually followed an episodic course with individuals recovering to normal between episodes. The latter was more likely to become a chronic illness with a majority of affected individuals not every fully recovering. These distinctions have broadly speaking held to this day.

Within the manic-depressive group, Kraepelin included all mood disorders, whether or not the person oscillated between manic and depressive poles. For this reason, a great number of individuals who have recurrent depressive disorders are diagnosed by many psychiatrists as having manic depressive illness. Others would distinguish between bipolar and unipolar mood disorders. Bipolar disorders, as the name implies, involve an affected individual presenting with evidence of having at some point had episodes of both mania and depression. In contrast, unipolar disorders are those illnesses in which there only appear to be depressive episodes. A unipolar disorder involving mania only is a theoretical possibility, with occasional cases reported.

At present, there is little distinguish bipolar from unipolar disorders other than episodes of mania. When they are depressed, both groups look indistinguishable, both respond to the same treatments and there are at present no biological markers of any sort that pick out the one group from the other. In part the problem may be that in practice one never knows whether one is dealing with a true unipolar disorder or a bipolar disorder, which has hitherto only presented with depressive episodes.

Somewhere between a third to a half of moderate to severe depressions appear to be associated with an episode of mania at some point during a subject’s lifetime (1). In addition to the problem noted above in attempting to determine just what is the true proportion of bipolar to unipolar affective disorders, there is a further problem, in that many episodes of ‘biological’ depression may be so mild as to go unnoticed by a general practitioner. Similarly there are episodes of hypomania (less than full-blown mania), which can be diagnosed retrospectively based on a clear history of a sustained period of several weeks during which the subject was elated, overactive and perhaps somewhat uninhibited, but during which the individuals behaviour neither led to a diagnosis nor hospitalisation.

There are two issues that arise in any consideration of the management of manic episodes – one is the active treatment of the manic episode itself and the other is prevention of further episodes of either mania or depression.

Contents

• Lithium
• Neuroleptics
• ECT
• Sodium Valproate
• Calcium Channel Blockers
• Acetazolamide
• Do Antidepressants Cause Mania?
• References
• Do You Need Help?

Lithium

At present the most specific treatment for mania is generally held to be lithium. Lithium is thought to be both a specific treatment for episodes of mania as well as episodes of depression, and it is also used in the prophylaxis (prevention) of further episodes of either mania or depression. The questions of dosage and side effects of lithium are sufficiently complex to merit a separate section.

Neuroleptics

In practice, neuroleptics, and in particular haloperidol or chlorpromazine, are often the first line of treatment for mania. The reason for this is that there is often a pressing need to contain the behaviour of individuals with mania, and neuroleptics in moderate large doses do this relatively quickly. Some of the largest doses of neuroleptics in use clinically are used just for this purpose.

Aside from immediate control, neuroleptics are often the only treatment given for an episode of mania. Therefore, given the risks associated with neuroleptic use, the question arises whether neuroleptics are therapeutic for mania. There is some dispute as to whether neuroleptics are therapeutic for mania. There is some dispute as to whether neuroleptics are specific treatments for mania or whether they simply contain the disorder until it resolves spontaneously. A number of authorities have argued that because neuroleptics are helpful in manic states, mania must involve a disturbance of dopamine neurotransmission. If this were the case, then neuroleptics would be a specific treatment for mania, but this argument is a circular one (2).

An alternative is that neuroleptics are of some therapeutic usefulness in mania without being specifically therapeutic. Just as attempts to engage depressed individuals in programmes of motivated activity will often bring about or assist a cure, so conversely the demotivating and immobilising effects of neuroleptics could be expected to assist the resolution of a manic episode by taking the wind out of the sails of affected individuals. Indeed it can be argued that neuroleptics may play a similar role to that which light plays in the treatment of depression. Arguably when light therapy works for depression, it does so by activating the sufferer. The opposite treatment for mania might involve putting a patient in a darkened room in order to deactivate them. In practice neuroleptics have a somewhat similar effect.

A fall back position would be that neuroleptics simply contain manic behaviour non-specifically, by virtue of their chemical strait-jacketing effect, until such time as the episode burns itself out.

This issue is not without importance for a number of reasons. One is that neuroleptics may have serious long term consequences (see Side Effects of Neuroleptics). Another is that the long-term treatment of a recurrent bipolar disorder requires engaging patients in the management of their own condition. This is something they are likely to be less willing to do, if they have been the victims of some of the regimes that may be inflicted on them in hospital. In recent years a number of groups of individuals have formed who see themselves as ’survivors’ of psychiatric treatment. Many of these individuals are people who have had manic episodes.

ECT

There has also been a tradition that ECT is both antimanic and antidepressant. There are controlled clinical trials to show that it is as effective as, if not somewhat superior to, antidepressants in the treatment of depression. Even in the case of depression, however, ECT is generally used as a treatment of last resort for severe depressive disorders or for situations that are life threatening (see The Neuroleptics). In the case of mania there are very few manic episodes that fail to respond to either lithium or neuroleptics and accordingly it has been difficult to produce satisfactory research evidence that ECT is specifically beneficial in mania. The rationale for using it has, until recently, stemmed from the fact it was used widely in the era before lithium and neuroleptics were introduce and was noted to be useful.

In recent years, this situation has been remedied. It is now clear that ECT is a specific and as effective as lithium in the treatment of mania and indeed the evidence suggests that, if anything, it is somewhat more effective than lithium for mania (3).

Carbamazepine (trade name – Tegretol) has been in widespread use for epileptic disorders and in particular for temporal lobe epilepsy for a number of years. Along with sodium valproate and a range of barbiturate compounds, it is widely prescribed for epilepsy. Compared to the barbiturates, it is less sedating and is non-addictive.

In addition to a use in epilepsy, carbamazepine is also used for a number of other purposes, such as a first line of treatment for trigeminal neuralgia. It has also been recommended for what is called dyscontrol syndrome, or episodic dyscontrol, a term which describes outbursts of behaviour that appear to occur for no obvious reason. It has been argued that such outbursts may actually be epileptic episodes without the normal convulsions, in some cases, rather than just temper tantrums. On this basis, carbamazepine has been used with some evidence for efficacy. In practice, however, EEGs are rarely done to check for epilepsy, and carbamazepine is used on a trial basis – if it seems to help it is continued and if not is stopped.

The most common use for carbamazepine, other than epilepsy, however, is in mania, particularly for episodes that do not respond to lithium. It is also used for mania and bipolar disorders characterised by dysphoria (irritability and paranoia) rather than elation and for rapidly cycling affective disorders.

Its side effects are dizziness, discoordination, double vision and lethargy. Dry mouth, nausea and diarrhoea or constipation may occur. It may cause sedation and may also produce skin rashes in up to 15% of takers.

In general a plasma level of between 4-12 µg/l is aimed at. Typically the actual dose that is needed to produce such a level may vary considerably. It is customary to start individuals off on a dose of 200 mg per day and increase very slowly – usually 200 mg per week. A dose of 800-1200 mg per day seems the commonest.

Carbamazepine may bring about a reduction in white cell count, and predispose to the development of fever and sore throats as a consequence. If there are signs of fevers, sore throats or infections of any sort, a white cell check should be done and, if low, it may be necessary to discontinue treatment. In general, blood counts and liver function tests should be done monthly while carbamazepine is being taken.

Carbamazepine induces liver enzymes. As a consequence, a number of other treatments/medications may be metabolised more rapidly, which may mean that a number of treatments, and in particular the contraceptive pill, do not work as well as before. Haloperidol and lithium may also be affected.

The precise mechanism of action of carbamazepine is unknown. There are some suggestions that it blocks calcium channel entry. Accordingly it should be used cautiously with calcium entry blockers such as verapamil (see The Management of Side Effects).

Sodium Valproate

Sodium valproate is another agent which was used in the first instance for the management of epilepsy. It is formulated in different ways in Europe, Britain and the United States. In the United States where it is used more frequently than elsewhere in the management of affective disorders, it is known as valproic acid. In recent years, it has come into use as an alternative to lithium and indeed in some places it has replaced carbamazepine as the first alternative to lithium.

It is used both for the management of acute episodes of mania and the prophylaxis of the recurrent episodes of a bipolar disorder. In acute mania, doses in the order of 1.2-1.6 g are used in divided doses. Up to two-thirds of patients can be expected to respond (4). There are some suggestions that as with carbamazepine episodes of mania characterised by dysphoria and irritability, rather than euphoria, may respond better to sodium valproate.

The side effects of valproate are weight gain (up to 50%), weakness (up to 30%), tiredness or drowsiness (up to 30%), a fine tremor (5-10%) and hair loss or hair change (10%). Older preparations of valproate were associated with an incidence of nausea in up to 40% and vomiting or abdominal pain in up to 25%. More recently developed preparations are enteric-coated and this has resulted in a much lower incidence of nausea of around 5%. There are suggestions of menstrual irregularities with valproate and of teratogenic effects on the developing foetus.

Valproate inhibitis liver enzymes and this can lead to increases in co-administered drugs. For the most part the co-administered drugs that have been looked at have been other anticonvulsants, but there also appear to be interactions with anticoagulants and salicylates. There is no knowledge about possible interactions with never agents such as the SSRIs or more recently introduced neuroleptics.

Calcium Channel Blockers

These are outlined in more detail in The Management of Side Effects. There have been a number of claims in recent years that they may be useful in mania. The evidence for this is inconclusive at present. It seems more likely that these drugs are atypical tranquillisers of some sort and therefore may be potentially of some use in manic or excited states without necessarily being specific to mania, in the way for example that lithium or ECT is. It can be noted that calcium channel blockers are also mildly anti-epileptic as as is carbamazepine. It seems likely, therefore, that they are doing much the same thing as carbamazepine. Exactly what this action is, however, is not clearly specified as of yet.

Acetazolamide

This is another anticonvulsant which acts to inhibit an enzyme called carbonic anhydrase. It is not widely used and there have only been a few reports claiming that it may be useful. In particular, however, these reports have claimed that it’s of some use for the kind of dreamy confusional psychoses that may occur post partum or perimenstrually.

Do Antidepressants Cause Mania?

There has been a tradition for many years that tricyclic or MAOI antidepressants may cause mania. It seems intuitively obvious that this should be the case. However, against this intuition is the face that both lithium and ECT, as well as carbamazepine, appear in some respects to be both antidepressant and antimanic. Based on this one might wonder whether all agents that were antidepressants should not also be antimanic. At present the only studies of tricyclic antidepressants given in mania suggest that they too may be antimanic (5). Why then the belief that antidepressants may cause mania?

This is partly because all mental health professionals have seen people taking antidepressants become elated. However, a number of studies recently have indicated that there has always been a natural incidence of manic episodes following episodes of depression, even before the availability of the antidepressants or ECT. The implication of this is that individuals recovering from a depression may swing into mania. The opposite also appears to be true in that a number of subjects recovering from mania appear to get depressed. Ordinarily such swings into mania and swings into depression tend to be relatively short-lived and mild

The effects of ECT and antidepressants on this process appear to be to abort what may be otherwise lengthy depressive episodes much more rapidly than would otherwise have been the case. This may lead to the occurrence of a manic swing earlier than would have happened. Such swings occur even on ECT or lithium which are effective antimanic treatments.

We tend to attribute, however, anything that happens to individuals who are on medication to the effects of the medication itself. Because of this there is a natural tendency to attribute episodes of mania that may occur on antidepressants to the action of those antidepressants. In contrast it is not impossible that tricyclic antidepressants and even monoamine oxidase inhibitors might be antimanic agents also.

There are two other factors that tend to obscure the picture. In the case of the tricyclic antidepressants there may be dissociative reactions. These are episodes of confusion, agitation and possible hyperactivity (see Side Effects of Antidepressants). They are more likely in an elderly group of patients. The agitation and hyperactivity may be diagnosed as mania, and the interference drawn that the drugs have caused this mania. However, such reactions ordinarily resolve rapidly once the offending drug is withdrawn whereas a true manic episode should last somewhat longer.

In the case of the monoamine oxidase inhibitors in some instances there may be stimulant effect resembling that produced by amphetamines. This will also resemble mania but differs from mania, in that the state wears off once the monoamine oxidase inhibitor is discontinued.

References

1. Healy D: The antidepressant era. Cambridge MA: Harvard University Press; 1987.
2. Healy D, Williams JMG: Moods, misattributions and mania. Psychiatr Dev 1989, 7:49-70.
3. Small J G, Klapper H H, Kellams J G; Electroconvulsive treatment compared to lithium in the management of manic stress. Archives of General Psychiatry, 45, 727-732. 1988
4. Balfour J A, Bryson H M; Valproic acid. A review of its pharmacology and therapeutic potential in indications other than epilepsy. CNS Drugs 1994 2, 144-173.
5. Angst J; Switch from depression to mania – a record study over decades between 1920 and 1982. Psychopathology 1985, 18, 140-154.