**4.2 Other positive signals related to mental disorders are mainly absent as ADRs in SPCs**

#### *4.2.1 Anxiety*

It is striking that no one of these positive signals detected are reported in SPCs. As an example of contrast, cerivastatin showed an elevated number of reports [2, 43] of signals as anxiety or emotional disorder never stated in factsheets. Atorvastatin also showed an emotional distress signal.

A diagnosis of hyperlipidemia and the beginning of statin treatment could lead to anxiety about high cholesterol and its consequences. However, it is difficult to identify which anxiety is due to the onset of the treatment and associated with the fear of cardiovascular health, and which one is associated with a real ADR by statins.

In general, there is conflicting evidence of a relationship between statins and mood [44]. Some authors associate anxiety with an increased likelihood of discontinuation with statins [45]. In some groups of patients with head and neck cancer, preexisting hyperlipidemia was associated with an increased risk of new-onset anxiety/depression [46].

However, avoiding the diagnosis of the illness and chronic treatment, uncertainties about the pharmacological mechanisms, risks to health, side effects, costs, and skepticism are considered barriers to the uptake of statins [47].

The association between anxiety and nonadherence to preventive therapies remains unclear, and some authors have investigated whether the somatic symptoms of anxiety predict statin nonadherence [48].

#### *4.2.2 Bipolar disorders*

Bipolar disorder signals only appeared with rosuvastatin.

It has been observed that the continued use of drugs such as low-dose aspirin, statins, and angiotensin agents was associated with decreased rates of incident mania/ bipolar disorder on both the outcome measures [49]. At least, as treatment, statins do not seem to exacerbate this cognitive dysfunction [50].

In patients with central nervous system metabolic disorders, it was hypothesized that statins may act as unmasking agents for latent neuromuscular disorders, as reported in cases of acute ataxia coincident with statin onset in individuals with bipolar disorder [51].

#### *4.2.3 Psychiatric symptoms and psychotic disorder*

It has an idea of the relation between the use of statins and preexisting psychotic disorders. The first meta-analyses published about that clarified that adjunctive therapy with statins could improve psychiatric symptoms, either negative symptoms or positive symptoms [52].

Data from the Norwegian spontaneous reporting system and from WHO's, an international database covering the period of 1988–1995, include reports of adverse drug reactions relating to psychiatric disorders (15% of the reactions to statins in the Norwegian database). Reactions include aggression, nervousness, depression, anxiety, sleeping disorders, and impotence. The pharmacological mechanisms are not elucidated but may be an effect of falling serum cholesterol [53].

#### *Early Signal Detection: Data Mining of Mental Disorders with Statins DOI: http://dx.doi.org/10.5772/intechopen.105504*

Another option is that statins show a strong association with inflammatory processes that may occur due to the disorder. This condition may cause increased inflammatory markers and concurrent psychiatric symptoms. Other factors such as gender, metabolic problems, or smoking can be associated with this increase in inflammatory markers [54].

This observation could be useful to elucidate the best statin for patients with different mental disorders. In the present study, psychiatric symptoms only appeared with simvastatin and psychotic disorder with simvastatin and lovastatin.

On the other hand, fluvastatin, pitavastatin, and pravastatin have no signals.

Some studies are in favor of statins used in combination with conventional psychotropic medications for various psychiatric disorders including depression, schizophrenia, and dementia [55].

#### *4.2.4 Suicide*

Atorvastatin, lovastatin, and simvastatin showed a signal of completed suicide (290 cases for atorvastatin and 283 for simvastatin). Simvastatin also presented signals for suicidal behavior, suicidal ideation (also rosuvastatin), and suicide attempt. It appears that statin, in particular, simvastatin, is a clear candidate for studying of suicidal conditions.

There are cases with simvastatin (various doses), atorvastatin (various doses), and lovastatin that reported mood/behavior change (violent ideation, irritability, depression, and suicide) that commenced following statin initiation and persisted or progressed with continued use. Problems resolved with drug discontinuation and recurred with rechallenge were attempted [56].

Aggressive reactions associated with statins are poorly documented in the literature, but they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the etiology of this psychiatric reaction [57].

#### **4.3 Limitations of the study**

The download of information on adverse drug reactions was carried out shortly before December 1, 2019, the date considered to be the start of the international pandemic by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Analyzing data before this date has the advantage of avoiding the potential and unknown interactions of the coronavirus or subsequent vaccines with pharmacological treatments.

It is known that the values of specificity and sensitivity are typically low with BCPNN methodology [23]. Nonetheless, it is acceptable with very high specificity and a low but conservative sensitivity as detected for typical positive signals for cerivastatin and other statins.

## **5. Conclusions**

Mental disorders detected and proposed in the present study to further investigation are insomnia for pitavastatin, pravastatin, and simvastatin; dementia for

atorvastatin and rosuvastatin; and suicide and psychotic disorders for atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.

Moreover, signals of central disorders as an affectation of senses for pitavastatin (hearing loss), pravastatin (visual impairment), atorvastatin (blindness), and simvastatin (ageusia) can act as confounding symptoms of mental disorders, and they would be interesting to analyze in clinical trials as early symptoms for statin interchange.

Surrendering to the low positive signals detected, fluvastatin, stands out as a candidate to contrast with the others.

## **Acknowledgements**

To the European University of Miguel de Cervantes (UEMC, Valladolid, Spain), for giving me time and permission to perform this study.

## **Conflict of interest**

The author declares no conflict of interest.
